Anti-inflammatory therapy with 3-indolinyl compounds



United States Patent Ofiflce 3,306,822 Patented Feb. 28, 1967 3,306,822ANTI-INFLAMMATORY THERAPY WITH 3-INDOL1NYL COMPOUNDS Tsung-Ying Shen,Westfieid, N.J., assignor to Merck 8: Co., Inc., Rahway, N.J., acorporation of New Jersey No Drawing. Filed May 20, 1963, Ser. No.281,813 4 Claims. (Cl. 167-65) This application is acontinuation-in-part of our copending application, Serial No. 164,615,filed January 5, 1962, now abandoned, which was in turn acontinuationin-part of Serial No. 97,434, filed on March 22, 1961, nowabandoned.

This invenion relates to a new method of treating inflammation and tocertain chemical compounds for such treatment. More specifically, thisinvention relates to the treatment of inflammation with 3-indolinylaliphatic acids having a l-aroyl or heteroaroyl substituent. Morespecifically also, it relates to a preferred new class of compounds fortreating inflammation in which the said l-aroyl or heteroaroylsubstituent carries at least one functional substituent.

The compounds used to treat inflammation in the general method of thisinvention have the formula:

in which R may be aromatic, aralkenyl, arylamino, or aryloxy, R may behydrogen, alkyl or aryl, R and R each may be hydrogen or alkyl, R may behydrogen, amino or hydroxyl, R may be hydroxyl, alkoxy, aryloxy,aralkoxy, dialkylarninoalkoxy, amino, hydroxyalkylamino, morpholino,alkylamino, arylamino, aralkylamino, diarylamino, diaralkylamino and OMwhere M is a cation, in and n each may be 0 or 1, n being 0 when m is 0;R may be hydrogen or alkyl and R and R each may be a furthersubstituent.

' The invention also includes as a separate embodiment certain preferredcompounds for use in the treatment of inflammation. Such compounds havethe structure:

Rs R7 R3 Eli-i OH(OH)mCOR R2 N R9 in which R may be aromatic aralkenylor aryloxy, R may be hydrogen, alkyl or aryl, R and R each may behydrogen or alkyl, R may be hydroxyl, alkoxy, aryloxy, aralkoxy,dialkylaminoalkoxy, amino, hydroxyalkylamino, morpholino, alkylamino,arylamino, aralkylamino, diarylamino, diaralkylamino and OM where M is acation, in may be 0 or 1 when m is 0, R may be hydrogen or alkyl and Rand R each may be a further substituent.

In the preferred compounds of the invention, R and R are hydrogen, alower alkyl, lower alkoxy, halogen, nitro, aralkyloxy, alkenyloxy,alkylthio, aralkylthio alkylsulfonyl, amino or substituted amino.Examples of the alkyls, aralkyloxy and alkoxys are methyl, ethyl,propyl, t-butyl, methoxy, ethoxy, i-propoxy, benzloxy and the like. Rand R are not limited to this class of substituents, however, and may,if desired, represent substituents such as aryl, aryloxy, hydroxy,mercapto, halo, pseudohalo such as CF CHF or other haloalkyls, nitro,amino, alkylamino, acylamino, haloalkyl, cyano, sulfarnyl, sulfoxide,amino-methyl, substituted amino methyl, carboxy and carboalkoxy groups.

A critical feature of the compounds used in the method of this inventionis the presence of an aroyl or hetero aroyl radical attached to the N-lposition of the indoline ring. These acyl groups in the preferredcompounds Which form an additional embodiment of this invention, arefurther substituted in the aromatic ring with functional substituents.Thus, suitable aroyl substituents are the benzoyl and riaphthoyl groups.The aromatic rings of such groups may contain, and in the preferredcompounds do contain at least one functional substituent. Thissubstituent may be a hydroxy or an etherifled hydroxy (hydrocarbonoxy)group such as a lower alkoxy, e.g. methoxy, ethoxy, isopropoxy,allyloxy, propoxy, an aryloxy or aralkoxy group, e.g. phenoxy,benzyloxy, halobenzyloxy, lower alkoxybenzyloxy and the like. It may bea nitro radical, a halogen such as chlorine, bromine, iodine orfluorine, an amino group or a substituted amino group, representativeexamples of which that might be mentioned are acylamino, amine oxide,ketirnines, urethanes, lower alkylainino, lower dialkylamino, amidine,acylated amidines, hydrazine or a substituted hydrazine, alkoxyaminesand sulfonated amines. Further, it may be a mercapto or a substitutedmercapto radical of the type exemplified by alkylthio groups such asmethylthio, ethylthio, and propylthio and arylthio or aralkylthiogroups, e.g. benzylthio and phenylthio. The N-l aroyl radical may behaloalkylated, as with a trifluoromethyl, trifluoroethyl,perfluoroethyl, B-chloroethyl or like substituent, acylated as withacetyl, propionyl, benzoyl, phenylacetyl, trifluoroacetyl and like acylgroups, or it may contain a haloalkoxy or haloalkylthio substituent. Inaddition, the invention embraces the use of compounds wherein the aroylradical contains a sulfamyl, benzylthiomethyl, cyano, sulfonamido ordialkylsulfonamido radical. Further, the aroyl group may contain acarboxy substituent, or a derivative thereof, such as an alkali metalsalt or a lower alkyl ester of the carboxy radical, an aldehyde, azide,amide, hydrazide and the like, or an aldehyde derivative of the typerepresented by acetals or thioacetals. In the most preferred type ofcompound included within the new compounds in this invention, the N-laroyl radical is benzoyl and the functional substituent is in the paraposition of the six-membered ring.

Alternatively, the N-l group may be a heteroaryl substituent, and moreprecisely a heteroaroyl substituent of the formula where Het representsa five. or six-membered heteroaromatic ring, preferably of less thanthree fused rings. Examples of such radicals are the furyl, thienyl,pyrryl, thiazolyl, thiadiazolyl, pyrazinyl, pyridyl, alkylpyridyl,pyrazolyl, imidazolyl, oxazolyl, pyrimidinyl and isoxazolyl rings.

The 3-indolinyl aliphatic acids used in the method described herein arepreferably lower aliphatic acids such as 3-indolinyl derivatives ofacetic, propionic, butyric, valeric, B-halopropionic, acrylic,4-pentenoic acid and like acids with no more than three carbonsseparating the carbonyl and the indoline ring, and preferably, no morethan two. When three carbons separate the indoline rings and thecarboxyl, the carbon next to the carbonyl may carry an amino or hydroxylgroup. Esters, salts and amides of such aliphatic acids are also usablein the invention. The esters are important intermediates in thesynthesis of the free acids, and in many cases are themselves ofimportance as end products. Among the preferred esters are the loweralkyl esters such as the methyl, ethyl, propyl or t-butyl compounds, thephenyl, the benzyl, the p-halobenzyl, dialkylaminoalkyl and like estershaving less than nine carbon atoms.

The salts of these new l-aroyl or heteroaroyl-3- indolinyl-loweraliphatic acids can be obtained by treatment of the free acid with baseunder mild conditions. In this manner there may be obtained alkali metalsalts such as the sodium and potassium, the aluminum or magnesium saltsor salts of alkaline earth metals, examples of which are barium andcalcium. Salts of organic amines such as dimethyla-mine, morpholine,methyl cyclohexylamine or glucosamine may be obtained by reacting theacid with the appropriate organic base. The amides included withinFormulas I and 11 above are conveniently synthesized by first preparingthe amide of a S-indolinyl lower aliphatic acid unsubstituted at thel-position and then acylating said compound by the process describedhereinbelow. Such amides are conveniently obtained by reacting the freeacid with urea or treating the appropriate acid chloride with ammonia oran alkylamine or other substituted amine to form an N-alkylamide orother substituted amide. Amides may also be prepared from the l-acylindolinyl acids by acid chloride formation and reaction with theappropriate amine.

The 3-position of the indoline nucleus may also carry as a secondsubstituent a lower alkyl group. Usually, however, it is hydrogen. Suchadditional substituents at the 3-position are introduced in theformation of the intermediate indoline before acylation as more fullydescribed below.

The suhstituents on the 2-position of the indoline ring nucleus may behydrogen although it is preferred that there be present at this positionof the molecule a hydrocarbon radical having less than nine carbonatoms. Lower alkyl groups such as methyl, ethyl, propyl or butyl are themost satisfactory but Z-phenyl and 2-benzyl substituted indolines arewithin the purview of this invention as are indolines having at the2-position an unsaturated aliphatic radical such as allyl or vinyl or acyclic aliphatic residue such as cyclohcxyl.

The following compounds are representative of those contemplated for usein this invention and which may be prepared by the procedures discussedhereinbelow:

Methyl (l-p-chlorobenzoyl-Z-methyl-5-methoxy 3-indolinyl)-acetate,

methyl (1-p-chlorobenzoyl-2,S-dimethyl 3 indolinyl) acetate,

methyl (l-p-methylthiobcnzoyl-2-methyl 5 methoxy-3- indolinyl -ace ate,

a-(l-p-chlorobenzoyl-2-methyl-S-methoxy 3 indolinyl) propionic acid,

( l p chlorobenzoyl 2 methyl-5-methoxy-3-indolnyl) acetic acid,

(1-benzoyl-2-methyl-5-methoxy-3-indolinyl) acetamide,

B [1-(2,4-dichlorobenzoyl)-2-methyl-5-methoxy-3-indolinyl)-propionicacid,

methyl [1-(2'-thenoyl) -2 -methyl-5-methoxy-3-indolinyl] acetate,

a-[l-(p-chlorobenzoyl)-2-ethyl 5 methyl-3-indolinyl] propionic acid,

[3- l-(2'-furoyl)-2,5-dimethyl-3-indolinyl] -propionic acid,

[3-[l-(nicotinoyl)-5-methoxy-3-ind-olinyl] propionic acid,

,8- l-(naphthoyl)-3-indolinyl] -propionic acid,

t-1-[1-(4-thiazolyl)-5-methox y- 3 indolinyl] propionamide and the like.

The l-aroyl or hetero-aroyl-3-indolinyl lower aliphatic acids andderivatives thereof described herein are synthesized in one method ofpreparation, by hydrogenation of an N -unsubstituted indole, followed byacylation of the resulting 3-indolinyl aliphatic acid, ester or amide.It is preferred to carry out the acylation on an ester or amidederivative of the lower aliphatic acid. In those cases where the freeacid is desired, the ester may be converted to the free acid or theintermediate l-unsubstituted indolinyl free acid can be directlyacylated. Where the acyl group is to contain a sulfur containingsubstituent, the latter course is preferred to avoid poisoning thecatalyst during the reduction. Unlike the corresponding indoles, theindoline hetero-nitrogen is basic enough to permit ready acylation byordinary methods, such as with acid halides or anhydrides in thepresence of a tertiary organic base such as pyridine, or even by aSchotten-Baumann acylation in aqueous caustic. The acyl group thusformed is sufficiently stable to permit saponification of ester groupsin the carboxylic side chain, so long as mild conditions are used.Conditions for such saponification are agitation in alcoholic or aqueouscaustic. Usually caustic soda of 2 N or 3 N strength and overnightagitation at room temperature are sufficient. Weaker base will usehigher temperatures and stronger base will require refrigeration. Thecaustic used may be any alkali or alkaline earth metal hydroxide or aquaternary ammonium hydroxide or even an aqueous solution of ammonia oran amine.

When the l-scyl indolinyl free acids are prepared by hydrogenation ofthe corresponding l-acyl indolyl free acids, the latter are prepared bythe special methods necessary in their case. These indole precursorsmust be synthesized by methods requiring more care. One convenientmethod of accomplishing the deesterification of the l-acyl indolylesters comprises acylation of the benzyl ester and subsequenthydrogenolytic removal of the benzyl ester. Alternatively, ether esterssuch as the t-butyl esters, or other tertiary other esters, which areamenable to selective removal by other treatment, such as heating above210 C. or by heating at 25-110 C. in the presence of a catalytic amountof an aryl sulfonic acid or other acids may be utilized. When, insteadof an ester, the amides of these acids are prepared, the free acids areformed by reaction of the amides with a stoichiometric quantity ofnitrous acid in an inert solvent.

The acylation reaction is preferably conducted in the indole series bytreating the a-(3-indolyl) lower aliphatic ester starting material withan alkali metal hydride, such as sodium hydride, to form e.g. a sodiumsalt and then intimately contacting said salt with an aroyl or hetero"aroyl acid halide in an anhydrous solvent medium. It is preferred toemploy solvents such as dimethylformamide, dimethylformamide-benzene,benzene, toluene or xylene. It is preferred to carry out the acylationof the indolyl acids at about room temperature although lowertemperatures may be employed if the particular reactants are undulysusceptible to decomposition.

An alternative method of acylating the 1-position in an indolyl ester isby use of a phenolic ester of the acylating', acid, such as thep-nitrophenyl ester. This latter is pre pared by mixing the acid andp-nitrophenol in tetrahydrofuran and adding dicyclohexyl carbodiimide intetrahydrofurane slowly. The dicyclohexylurea which forms is removed byfiltration and the nitrophenylester is recovered from the filtrate.Alternatively there can also be used the anhydride, azide orthiophenolic ester of the acylating acid. Whichever is used, theacylation of the 3-indolyl lower aliphatic ester starting material isachieved by forming a sodium salt of said material with sodium hydridein an anhydrous solvent and adding the nitrophenylester.

The l-acyl indole acids thus prepared are then hydrogenatedcatalytically to form the 2,3-dihydroindole (i.e., indoline) acids usedin this invention. Such reduction is carried out at low pressure andambient temperatures over a catalyst such as palladium on charcoal orplatinum oxide. When the reduction to the indoline is carried out beforeacylation, a process preferred because it eliminates the difficultiesinherent in the acylation and saponification of the indole acid esters,the reduction is carried out over a nickel catalyst at higher pressuresand ambient ternperatures. Such reductions are usually preferred in aninert solvent such as glacial acetic acid, at room temperature at about2000 psi.

The l-aroyl or hetero-aroyl-3-indolinyl lower aliphatic acid compoundsused in this invention have a high de gree of anti-inflammatoryactivity, especially the novel l-substituted aroyl compound, and areeffective in the prevention and inhibition of granuloma tissueformation. Certain of them possess this activity in high degree and areof value in the treatment of arthritic and dermatological disorders andin like conditions which are responsive to treatment withanti-inflammatory agents. For these purposes, they are normallyadministered orally in tablets or capsules, the optimum dosagedepending, of course, on the particular compound being used and the typeand severity of infection being treated. AlthOugh the optimum quantitiesof these compounds of this invention to be used in such manner willdepend on the compound employed and the particular type of diseasecondition treated, oral dose levels of preferred compounds in the rangeof -4000 mg. per day are useful in control of arthritic conditions,depending on the activity of the specific compound and the reactionsensitivity of the patient.

The indolinyl aliphatic acid compounds employed as starting material inthe reaction discussed above, and having the formula! where R R R R R Rand R have the previously defined meanings and R is an alkoxy radical ora substituted or unsubstituted amide radical may be synthesized invarious ways. In general, they can be formed from the correspondingindole by reduction as described below. The indoles can be synthesizedby the following methods. When R is hydrogen, methyl, aryl or aralkyland R is hydrogen it is preferred to form such compounds by reactingtogether an appropriately substituted phenylhydrazine and an ester oramide of the formula shown below to form an intermediate phenylhydrazonewhich cyclizes under the reaction conditions to the indole compounds:

The reaction is normally carried out in a lower alkanol such asmethanol, ethanol, isopropanol or butanol containing an acid such ashydrochloric, hydrobromic, sulfuric or acetic acid or in aqueous mineralacid such as concentrated hydrochloric, hydrobromic, sulfuric or aceticaid, or other Lewis acids such as ZnCl B1 SnCL; and the like. The acidserves as a catalyst in the condensation and ring closure reactionsleading to the indole. When the ester or amide starting material is anester, the nature of the ester is not critical, although it is preferredto utilize a lower alkyl ester, e.g., the methyl, ethyl, propyl,isobutyl or isopropyl compound. To avoid the possibility oftransesterification the alcohol used as the solvent medium is preferablythe same as the alcohol moiety of the ester. When R is hydrogen, it isconvenient to employ the aldehyde in the form of an acetal, e.g., methylwy-dimethoxy butyrate. An acid addition salt of the phenylhydrazinereactant, for example the hydrochloride, is normally preferred over thefree base for pratcical reasons, although such salts and the base areequivalent in the reaction itself.

Formation of the 3-indolyl aliphatic acid, or ester thereof, is broughtabout at elevated temperatures, good results being obtained by refluxingthe reaction mixture for at least about 15 minutes. Longer reactiontimes are not harmful and may be used if desired. The desired compoundis recovered from the reaction mixture and purified by techniques suchas solvent extraction, chromatography and/or distillation. Since theindole esters are low melting solids, they are conveniently purified bydistillation under reduced pressure. They are saponified by treatmentwith an alkali metal hydroxide.

The substituted phenylhydrazines employed as one of the startingmaterials in this synthesis are prepared by known methods. Oneconvenient method is by diazotization of the appropriately substitutedaniline to give the diazo compound, treatment of the latter withstannous chloride to form a tin complex, and decomposition of thiscomplex to the phenylhydrazine with sodium hydroxide.

Alternatively, it is possible to first produce an indole where R and Rhave the same meaning, and then introduce the carboxylic acid residue atthe 3-position. This is accomplished by treating the indole of FormulaVI under Mannich reaction conditions with formaldehyde-dialkylamine toproduce a substituted gramine, subsequently reacting this lattercompound with an alkali metal cyanide in a lower alkanol, and finallyhydrolyzing with a strong base such as sodium or potassium hydroxide.

While this method of introducing the aliphatic acid residue at the3-position after elaboration of the indole ring is, of course, generallyapplicable to compounds having the structure shown above, it isparticularly useful for making compounds of this invention wherein R isan alkyl radical other than methyl, such as the 2-ethyl, 2- propyl, andlike substances. Compounds of Formula VI are readily prepared followingthe procedures set forth in columns 2 and 3 of US. Patent No. 2,825,734.Products where R is acyloxy, halo, carboxy, carbalkoxy, alkyl, aryl,aralkyl, nitro or hydrocarbonoxy are prepared via the synthesisbeginning from a substituted 2-nitro benzaldehyde or 2-nitrotoluene.

The synthesis of various compounds of this invention having on theindoline ring system a S-substituent which has a nitrogen attached tothe homocyclic ring of the indoline is generally based on thecorresponding S-nitroindole. This is transformed into the desiredS-substituent. Such transformation may be before or after acylation ofthe 1-position, depending on the extent to which the desiredS-substituent may interfere with the acylation. If such interference ispossible, the l-acylation should be carried out on the S-nitro indoleand the nitro later transformed into the desired S-substituent. In anycase, the transformation must take place before reduction of the indoleto the indoline, since such reduction Will also reduce the nitro to anamino group. I

Such transformation of the nitro group into other nitro gen substituentscan be carried out in a number of ways. Reduction of the S-nitro groupsgives a S-amino group. Reaction of the amino with alkyl halides givemono and dialkyl amino groups. If the alkyl halide is a dihaloalkylenegroup (e.g., pyrrolidino) is formed. Similarly, bis(,8-chlorethyl)etherwill give an N-morpholino compound. Alkylation can also be carried outsimultaneous with reduction, as e.g., with formaldehyde and Raney nickeland hydrogen. Acylation can similarly be carried out on the S-aminocompounds or on the S-nitro (with simultaneous reduction) to giveS-acylamido compounds.

The S-amino group can be reacted with isocyanates to give S-ureidocompounds.

The following examples are given for purposes of illustration and not byway of limitation:

EXAMPLE 1 A. Ethyl-ot-(Z-mezltyl--mcl/z0xy-3-ind0lyI)-pr0pi0nate Asolution of 25 g. of p-methoxyphenylhydrazine hydrochloride and 20 g. ofethyl ot-methyl levulinate in 250 ml. of 2 N ethanolic hydrochloride isheated on a steam bath for a few minutes. An exothermic reaction takesplace with the separation of ammonium chloride. The reaction flask isremoved from the steam bath and the mixture allowed to reflux gentlyuntil the initial reaction subsides. The mixture is again heated on asteam bath under reflux for 30 minutes, and then concentrated in vacuoto a volume of about 80 ml. The concentrate is diluted with about 400ml. of water and extracted with ether. The resulting ethereal extract isWashed with a saturated solution of sodium bicarbonate, and with water,and dried over anhydrous sodium sulfate. The dried solution is filteredand evaporated to a dark brown syrup which is purified by chromatographyover about 1 lb. of acid-washed alumina in a 2% ID. column usingmixtures of ether and petroleum ether (v./v. 1:9 to 1:1) as eluent. Thelight yellow syrup so obtained is distilled in a short-path distillationapparatus and the product collected at HP. 150153 C. (0.25 mm.). Thedistillate of ethyl-a-(Z-methyl-S-methoxy 3 indolyl)-propionatecrystallizes on trituration with petroleum ether, MP. 53- 55.5 C. Onrecrystallization from a mixture of ether and petroleum ether themelting point is unchanged.

Calcd. for C H O N: C, 68.94; H, 7.33; N, 5.36. Found: C, 69.23; H,7.31; N, 5.60.

When the methyl, propyl, isopropyl or benzyl ester of a-methyl levulinicacid is employed in the above reaction in place of the ethyl ester,there is obtained methyl-a-(2- methyl 5 methoxy-3-indolyl)-propionate,propy1-u-(2- methyl-5-methoxy-3-indolyl) propionate, isopropyl-a-(2-methyl 5 methoxy-3indolyl)-propionate, respectively. Alternatively, whenan ester of levulinic acid is used as starting material in the aboveprocess, the corresponding ester ofa-(2-methyl-5-meth0xy-3-indolyl)-acetic acid is obtained.

B. Ethyl-oc-(2,5-dimethyl-3-ind0lyl)-pr0pi0nate g. ofp-methylphenylhydrazine hydrochloride and 20 g. of ethyl m-methyllevulinate are added to 250 ml. of 2 N ethanolic hydrogen chloride andthe mixture warmed until reaction sets in. After the initial exothermicreaction stops, the mixture is refluxed for about /2 hour and thenconcentrated in vacuo to about /3 volume. 400 ml. of water are added andthe aqueous solution extracted with ether. The ether extracts are Washedwith sodium bicarbonate solution, and with water, then dried over sodiumsulfate. The ether solution is concentrated to a small volume in vacuoand chromatographed over acid-washed alumina (1 lb. of alumina in a 2%"ID. column). The material eluted with ether-petroleum ether (v./v. 9:1to 1:1) is distilled in a short-path distillation apparatus.Ethyl-tx-(2,5-dimethyl-3-indolyl) propionate distills at 150170 (bathtemp.)/1 mm., and crystallizes on trituration with petroleum ether, M.P.88 88.5 C.

When a lower alkyl or benzyl levulinate is employed in place of ethyla-methyl levulinate, lower alkylorbenzyl-(2,5-dimethyl-3-indolyl)-acetate is produced.

EXAMPLE 2 A suspension of 2.3 g. (0.046 m.) of 50% sodiumhydride-mineral oil in 250 m1. of dimethylformamide is stirred for 20minutes under nitrogen with ice-cooling. Then 8.64 g. (0.035 m.) ofethyl-a-(Z-methyl-S-methoxy- 3-indolyl)-propionate is added and themixture stirred for 20 minutes. 8.6 g. (0.046 m.) of p-methylthiobenzoylchloride in 50 ml. of dimethylformamide is added dropwise over a periodof minutes. The mixture is stirred in an ice-bath for 5 hours undernitrogen. It is then poured into a mixture of 500 ml. of ether, 5 ml. ofacetic acid and 1 l. of iced water. The organic products are extractedwith 3 x 300 ml. of ether. The ether solutions are combined and washedwith a large quantity of water, and dried over sodium sulfate. Thesolution is filtered, evaporated to near dryness and the residue chargedonto a 300 g. alumina column. Theethyl-a-(l-p-methylthiobenzoyl-Z-methyl-S-methoxy 3 indolyl)-propionateis eluted with 10% ether in petroleum ether. It is obtained as a yellowoil on concentration of the eluates to dryness.

The p-methylthiobenzoyl chloride starting material is obtained byheating a mixture of 27 g. (0.15 m.) of pmethylthiobenzoic acid and 21.4g. (0.18 m.) of thionyl chloride on a steam bath for 1 hour. About 20ml. of benzene is then added and boiled off. The remaining solution iscentrifuged and diluted with petroleum ether. On cooling, the acidchloride separates, M.P. 44 C.

When methyl-(2-methyl-5-methoxy-3-indolyl) -acetate is employed as thestarting material in the above process, there is obtainedmethyl-(1-p-methylthiobenzoyl-Z-methyl-5-methoxy-3 -indolyl -acetate.

EXAMPLE 3 Methyl-a-(1-p-clzlorobenzoyZ-Z-methyl-5-merh0xy- 3-ind0lyl)acetate To 3.9 g. (0.078 m.) of 51% sodium hydride-mineral oil suspendedin 150 ml. of distilled dimethylformamide, in a 1 liter 3-neck flask, isadded with stirring at 0 C., 9.5 g. (0.040 m.) ofmethyl-(2-methyl-5-methoxy-3- indolyl)-acetate in 150 ml. ofdimethylformamide. The mixture is allowed to stir for 1 hour and then9.1 g. (0.052 m.) of p-chlorobenzoyl chloride in ml. ofdimethylformamide is added dropwise over a period of 30 minutes. Thereaction mixture is stirred another 30 minutes at 0 C. and then allowedto stand 12 hours in the cold.

The reaction mixture is then filtered and the solids washed with ether.The ether is added to the filtrate which is then washed with Water anddried over sodium sulfate. After filtering off the sodium sulfate,approximately g. of acid-washed alumina is added to the etherealsolution and this mixture concentrated to dryness.

The indole-coated alumina is then packed on top of a column of 400 g. ofalumina. The column is eluted with petroleum ether containing increasingamounts of ethyl ether.Methyl-a-(1-p-chlorobenzoyl-2-methyl-5-n1ethoxy-3-indolyl)-acetate iseluted with 15% ether-petroleum ether. These latter eluates are combinedand concentrated to dryness. Recrystallization of the residue frombenzene-petroleum ether yields substantially puremethyl-e4l-p-chlorobenzoyl 2 methyl-S-methoxy-3- indo1yl)-acetate, MP.99100 C.

Carrying out the above-noted process with ethyl-a-(2-methyl-5-methoxy-3-indolyl)-propionate or benzyl-a-(2, S-dimethyl 3indolyl)-propionate yields, respectively, ethyl-a-(l-p-chlorobenzoyl 2methyl-5-methoxy-3-indolyl)-propionate andbenzyl-ot-(1-p-chlor0benzoyl-2,5- dimethyl-3 -in dolyl -propionate.

EXAMPLE 4 A mixture of 100 ml. of dimethylformamide, 5.2 g. (0.02 m.) ofethyl-oc-(2-methyl-5-methoxy-3-indolyl)- propionate and 1.2 g. (0.025m.) of sodium hydride in mineral oil (50% dispersion) is stirred in anice-bath under nitrogen for 1 hour. A solution of 4.0 g. (0.02 m.) of2-methyl-4-methylthiobenzoyl chloride (prepared from the acid, MP.159-162 C., and thionyl chloride) and 25 ml. of dimethylformamide isthen added during max.

EXAMPLE To a solution of 5.22 g. of ethyl-a-(2-methyl-5-methoxy-3-indolyl)-propionate in 20 ml. of dimethylformamide is added asuspension of 1.2 g. of 51% sodium hydride in mineral oil in 40 ml. ofdimethylformamide. After 1 hour of stirring at room temperature, asolution of 2.88 ml. of benzoyl chloride in ml. of dimethylformamide isadded to initiate a mild exothermic reaction with precipitation ofsodium chloride. The reaction mixture is stirred for 6 hours followed bystanding overnight. The mixture is poured into about 200 g. of ice andextracted with ether three times. The ethereal solution is washed withwater, sodium bicarbonate and dried over potassium carbonate. Afterfiltration the solution is evaporated to a syrup and chromatographed ona column of 100 g. of acid-washed alumina, using mixtures ofbenzene-petroleum ether (2:1 to 3:1 v./v.) as eluent. A total of 1.06 g.of ethyl-ot-(1-benzoyl-2-methyl- 5-methoxy-3-indolyl)-propionate isobtained as a thick yellow oil. sorption near the 2.8-3 region but showsstrong C=O absorptions at 5.8 and 5.95; characteristic for ester andamide functional groups, respectively.

EXAMPLE 6 Ethyl-a-(I-p-c/zlorobenzoyl-Z-metlzyl-S-methoxy- 3-ind0lyl)-propi0nate 13 g. of ethyl-(2-methyl-5-methoxy-3-indolyl)-propionate isadded to a mixture of 2.5 g. of 51% sodium hydride-mineral oil emulsionin 240 ml. of dimethylformamide. The resulting mixture is stirred atroom temperature for 30 minutes and then a solution of 8.75 g. ofp-chlorobenzoyl chloride in 50 ml. of dimethylformarnide is added slowlythereto over a 40-minute period. The mixture is then stirred in anice-bath for 4 hours under nitrogen. It is then poured into a mixture ofether, acetic acid and water as described in Example 2. Following thework-up procedure and using a 200 g. column of alumina for thechromatography step, and eluting with a mixture of 1:1 benzene-petroleumether, ethyl-u-(l-pchlorobenzoyl 2 methyl 5methoxy-3-indolyl)-propionateis obtained as a yellow oil.

EXAMPLE 7 (1-benzoyl-Z-methyl-5-meth0xy-3-ind0lyl)-acetic acid A. Asolution of g. of methyl-(2-methyl-5-methoxy- 3-indolyl)-acetate and 0.2g. of sodium in 60 ml. of benzyl alcohol is slowly fractionated over aperiod of 4 /2 hours through a Vigreux column to remove methanol. Theexcess benzyl alcohol is then removed by distillation at 60 C. (2.5 mm.)to give a residue of 18.6 g. of benzyl-(2-methyl-5-methoxy-3-indolyl)-acetate.

B. 10 g. of the benzyl ester obtained above is added to 3.3 g. of 51%sodium hydride-mineral oil emulsion in 260 ml. of dimethylformamideaccording to the procedure of Example 2. This mixture is treated asdescribed in that example in 7.7 ml. of p-chlorobenzoyl chloride and thereaction mixture worked up by the above-described process using achromatographic column of 340 g. of

The infrared spectrum shows no NH ab- EEO-632% 10 alumina and elutingwith 2030% ether in petroleum ether. From these eluates there isobtained benzyl-(1- benzoyl 2 methyl 5 methoxy-3-indolyl)-acetate, M.P.9l92 C.

C. 1.5 g. of the ester obtained in Part B above is added to 20 ml. ofethyl acetate containing a drop of acetic acid and reduced catalyticallyat room temperature in the presence of palladium on charcoal catalyst.When the reduction is complete the catalyst is removed by filtration andthe filtrate evaporated to a crystalline residue. This residue isrecrystallized from aqueous ethanol to givel-benzoyl-(2-methyl-5-methoxy-3-indolyl)-acetic acid, M.P. 172173 C.Alternatively, the residue obtained on removal of the reaction solventmay be purified by dissolving in chloroform and precipitating byaddition of petroleum ether to the chloroform solution.

EXAMPLE 8 10.5 g. of ethyl-a-(2-methyl-5-methoxy-3-indolyl)-propionateis added to a suspension of 2.2 g. of 51% sodium hydride-mineral oilemulsion in 240 ml. of dimethylformamide. After stirring for minutes,7.5 g. of p-fluorobenzoyl chloride is added thereto slowly over a-minute period, and the resulting mixture stirred for 40 minutes at 1015C. The reaction mixture is then poured into 400 ml. of water and theproduct isolated as described in Example 4 to give substantially purethy1-Dt-( l-p-fluorobenzoyl-2-methyl-5-methoxy-3-indolyl)-propionate.

When the above process is carried out by reacting the sodium salt ofmethyl-ix-(Z-methyl-S-methoxy-3-indolyl)- propionate withp-trifiuoromethylbenzoyl chloride, there is obtained methyl 0c (1 ptrifluoromethylbenzoyl 2- methyl-5-methoxy-3-indolyl)-propionate.

EXAMPLE 9 to the corresponding free acids by the procedure of Example7C.

EXAMPLE 10 1-p-c/zlorobcnzoyl-Z-methyl-5-metl10xy-3-ind0lylacetic acidA. 2-methyl-5-methoxy-3-indolylacctic anhydridc.Dicyclohexylcarbodiimide(10 g., 0.049 mole) is dissolved in a solution of2-methyl-5-methoxy-3-indolylacetic acid (22 g., 0.10 mole) in 200 ml. ofTHE, and the solution is allowed to stand at room temperature for 2hours. The precipitated urea is removed by filtration, and the filtrateis evaporated in vacno to a residue and flushed with Skellysolve B. Theresidual oily anhydride is used without purification in the next step.

B. t-Buryl Z-methyl S-methoxy 3-z'nd0lylacctate.t Butyl alcohol (25 ml.)and fused zinc chloride (0.3 g.) are added to the anhydride from part A.The solution is refluxed for 16 hours and excess alcohol is removed invacuo. The residue is dissolved in ether, washed several times withsaturated bicarbonate, water, and saturated salt solution. After dryingover magnesium sulfate, the solution is treated with charcoal,evaporated, and flushed several times with Skellysolve B for completeremoval of alcohol. The residual oily ester (18 g., 93%) is used withoutpurification.

C. t-Butyl 1-p-chl0r0benz0yl- Z-nzcthyl S-metlzoxy 3- indZylacetale.Astirred solution of ester (18 g., 0.065 mole) in dry DMF (450 ml.) iscooled to 4 in an ice bath, and sodium hydride (4.9 g., 0.098 mole, 50%susp.) is added in portions. After 15 minutes, p-chlorobenzoyl chloride(15 g., 0.085 mole) is added dropwise during 10 minutes, and the mixtureis stirred for 9 hours without replenishing the ice bath. The mixture isthen poured into 1 l. of acetic acid, extracted with a mixture of etherand benzene, washed thoroughly with water, bicarbonate, saturated salt,dried over magnesium sulfate, treated with charcoal, and evaporated to aresidue which partly crystallizes. This is shaken with ether, filtered,and the filtrate is evaporated to a residue (17 g.) which solidifiesafter being refrigerated overnight. The crude product is boiled with 300ml. of Skellysolve B, cooled to room temperature, decanted from somegummy material, treated with charcoal, concentrated to 100 ml, andallowed to crystallize. The product thus obtained (10 g.) isrecrystallized from 50 ml. of methanol and gives 4.5 g. of analyticallypure material, M.P. 1034.

D. 1-p-chlorobenzoy[-2-mcthyI-5-me1Iz0xy-3-ind0lylacetic acid.A mixtureof 1 g. ester and 0.1 g. powdered porous plate is heated in an oil bathat 210 with magnetic stirring under a blanket of nitrogen for about 2hours. No intensification of color (pale yellow) occurs during thisperiod. After cooling under nitrogen, the product is dissolved inbenzene and ether, filtered, and extracted with bicarbonate. The aqueoussolution is filtered with suction to remove ether, neutralized withacetic acid, and then acidified weakly with dilute hydrochloric acid.The crude product (0.4 g., 47%) is recrystallized from aqueous ethanoland dried in vacuo at 65; M.P. 151.

EXAMPLE 111-p-metl1yIthi0benzoyl-2-methyl-5-melh0xy-3-indoIyla-propionic acid A.Z-methyl S-melhoxy 3-i/zd0Zyl-u-pr0pi0nicanlzydride.Dicyclohexylcarbodiimide (9 g. 0.44 mole) is dissolved in asolution of 2-methyl-5-methoxy-3-indolyl-apropionic acid (21 g., 0.09mole) and 200 ml. of THF, and the solution is allowed to stand at roomtemperature for 2 hours. The precipitated urea is removed by filtration,and the filtrate is evaporated in vacuo to a residue and flushed withSkellysolve B. The residual oily anhydride is used without purification.

B. t-Bulyl Z-methyl-5-mcth0xy-3-ind0lyl-a-propionate.- t-Butyl alcohol(25 ml.) and fused zinc chloride (0.3 g.) are added to the aboveanhydride. The solution is refluxed for 16 hours, and excess alcohol isremoved in vacuo. The residue is dissolved in ether, washed severaltimes with saturated bicarbonate, water and saturated salt solution.After drying over magnesium sulfate the solution is treated withcharcoal, evaporated, and flushed several times with Skellysolve B forcomplete removal of alcohol. The residual oil ester (14 g.) is usedwithout purification.

C. t-Butyl 1p-methy1thiobenzoyl-Z-methyl-S-mcthoxy-3-ind0lyl-a-pr0pi0nate.--A stirred solution of ester from Part B (20 g.,0.69 mole) in 450 ml. of dry dimethylformamide is cooled to 4 in an icebath and sodium hydride (5.2 g., 0.10 mole, susp. )is added in portions.After the mixture is stirred for 10 minutes, p-methylthiobenzoylchloride (M.P. 51; 17 g., 0.091 mole) is added in portions during 10minutes, and the mixture is stirred for 7 hours at room temperaturewithout replenishing the ice bath. The mixture is then poured into 1 l.of 5% acetic acid, extracted with ether, washed thoroughly with water,

bicarbonate, saturated salt solution, dried over magnesium sulfate,treated with charcoal, and evaporated in vacuo to a residue (33 g.).This is dissolved in ether, mixed With g. of acid washed alumina, andevaporated in vacuo to dryness, which is placed above a column of 300 g.of acid washed alumina in Skellysolve B. After washing with SkellysolveB, the product is eluted with 5% ether-Skellysolve B, and is obtained asa yellow oil (11 g., 36%).

D. I-p-melhylrlziobenzoyl Z-znethyl S-metlzoxy 3-indolyl-ct-propz'onicacid.-The pyrolysis is carried out in the same manner as with t-butyli-p-chlorobenzoyl-2-methyl' 5-methoxy-3-indolyl acetate (of Example1013). The product is recrystallized from aqueous ethanol or benzene-Skellysolve B; M.P. -6".

EXAMPLE 12 Lp-clzlorobenzoyl-Z-methyl-5-methoxy-S-irzdolyla-prop ionicacid A. To a solution of 20.0 g. (0.07 mole) oft-butyla(2-methyl-5-methoxy-3-indolyl)-propionate in 270 ml.dimethylformamide is added in small portions 7.0 g. (0.14 mole) of 51%sodium hydride in mineral oil under N with stirring and ice-cooling.After 15 minutes, 17.5 g. (0.10 mole) of the p-chlorobenzoyl chloride isadded dropwise, a white precipitate separates out almost immediately.The mixture is stirred at 0 for 2 hours and is allowed to stand in thecold room overnight. The next morning the mixture is filtered anddiluted with ether. One-half of the solution is Washed with water,sodium bicarbonate, Water successively and dried over sodium sulfate.The dried solution is concentrated to a syrup which i chromatographed on400 g. of acid-washed alumina. After mineral oil and trace of impurityis eluted by petroleum ether and 5% ether in petroleum ether, thedesired product is obtained by elution with 10% ether in petroleum etheras yellow oil. The other half is similarly treated.

B. The above ester and a few pieces of porous plate chips are placed ina flash submerged in an oil bath. A steady stream of N is introducedinto the test tube through the opening while the temperature of the oilbath is slowly raised to 215. After /2 hour at 215", the mixture isdissolved in ether, filtered and washed with sodium bicarbonate. Thebicarbonate extract is acidified with dilute hydrochloric acid, and theprecipitate is taken into ether, washed with water, dried over sodiumsulfate and evaporated to dryness. The solid residue is recrystallizedfrom a mixture of benzene and petroleum ether to give the desired acid,M.P. 8788.

EXAMPLE l3 A. In a 500 ml. round bottom flask (all equipment flamedried) is added 13.9 g. of p-nitrophenol and 12.3 g. isonicotinic acidin 250 ml. dry tetrahydrofuran. Through a dropping funnel is added over30 minutes 20.6 g. of dicyclohexylcarbodiimide in 100 ml. of drytetrahydrofuran. The reaction is allowed to run overnight with stirring.The dicyclohexylurea which forms during the reaction is filtered. Thefilter cake is washed with dry tetrahydrofuran. The solution isevaporated in dryness. The solid is taken up in benzene and washed withsodium bicarbonate solution and then with Water and dried over anhydroussodium sulfate. The solution is concentrated under vacuum to dryness.The solid p-nitrophenylisonicotinate is then recrystallized frombenzene, M.P. 126- 127 C.

B. In a 250 m1. round bottom flask (flame dried equipment) is placed at0 C. with nitrogen, 100 ml. of dry dimethylformamide with 10.5 g. ofi11ethyla-(2-methyl- S-methoxy-E-indolyl) acetate. To this is added 2.5g. of 50% sodium hydride mineral oil mixture. After the mixture isstirred for 30 minutes there is added over 15 minutes a solution of .11g. of p-nitrophenylisonicotinate in 50 ml. dry dimethylformarnide. Thereaction mixture is stirred for 4 hours at C. under nitrogen followed bystirring under nitrogen at room temperature over night. The reactionmixture is then poured into an ice waterether solution containing a fewml. of acetic acid and the layers are separated. The aqueous phase iswashed with ether and the ether extracts are combined. To the etherlayers is added a saturated solution of hydrogen chloride gas in dryether. The ether is decanted off, leaving a heavy oil. The oil is washedwith ether followed by an addition of aqueous sodium bicarbonatesolution. The product is then extracted with ether. The ether layer isdried over anhydrous sodium sulfate and concentrated to dryness. Theproduct is crystallized from dry ether, M.P. 114115 C.

Micr0analysis.Calc. C, 67.45; H, 5.37; N, 8.28. Found: C, 67.67; H,5.50; N, 8.14.

EXAMPLE 14 Methyl (2-methyl-5-nitr0-3-ind0lyl )acetate A solution of 40g. of levulinic acid in 300 ml. of hot water is added to a solution of65 g. of p-nitrophenylhydrazine hydrochloride in 700 ml. of hot waterwith stirring. After about one-half hour, the hydrazone derivative iscollected in a filter, washed with water and dried at 110 in vacuo. Theyield is 84 g., M.P. 175-179".

An amount of 42 g. of the above hydrazone is added to a solution of 120g. of fused zinc chloride in 100 ml. of absolute ethanol and the mixtureis refluxed for 18 hours. The cooled solution is poured into dilutehydrochloric acid with stirring, and the insoluble gummy materialseparated is extracted with hot ethanol. The ethanolic extract isevaporated in vacuo to a syrup, which is redissolved in ether. The ethersolution is extracted with sodium carbonate several times. Acidificationof the aqueous solution gave a crude product which recrystallizes fromchloroform to give (2-methyl-5-nitro- 3-indolyl)acetic acid, M.P. 238.

The above acid is treated with a mixture of 3 g. of sulfuric acid and 40ml. of methanol at the reflux temperature for 6 hours. The methyl esteris obtained as a yellow crystalline product, M.P. 13240 afterrecrystallization from benzene.

Similarly, methyl-a-(2-methyl-5-nitro-3-indolyl)- propionate is preparedby using an equivalent amount of amethyl levulinic acid as the startingmaterial.

EXAMPLE Methyl(Z-methyl-5-amin0-3-indolyl)acetate 3 g. ofmethyl(Z-methyl-5-nitro-3-indolyl) acetate is dissolved in 300 ml. drymethanol and reduced in hydrogen in an autoclave with Raney nickel ascatalyst. After the theoretical amount of hydrogen is taken up thecatalyst is removed by filtration. The catalyst and reaction flask arewashed with methanol. The methanol solution is evaporated to dryness.The product is crystallized from benzene, M.P. 144-145".

Micr0analysis.--Calc. C, 66.03; H, 6.47; N, 12.84. Found: C, 65.96; H,6.29; N, 12.56.

EXAMPLE 16 Methyl[2-methyl-5-(I -pyrr0lidin0)-3-ind0lyl] acetate In a125 ml. flask is placed 80 ml. of ethanol. To this is added 1.0 g. ofmethyl (2-mcthyl-5-amino3-indolyl) acetate, 0.99 g. of 1,4-dibromobutaneand 0.975 g. of anhydrous sodium carbonate. This mixture is stirred atreflux temperature in a nitrogen atmosphere for 6 hours. The reactionmixture is then filtered and the filtrate is concentrated in vacuo to asmall volume and diluted with ether. This solution is then washed withwater 2 dried With anhydrous sodium sulfate and concentrated in vacuo todryness. The product is absorbed on 6 g. of silica gel. The product isthen chromatographed over g. of silica 14 gel using as elutant fromv./v. 3:1 ether-petroleum ether to ether. The eluted material iscombined and crystallized from benzene-Skellysolve B, M.P. 117118.

Micr0analysz's.Calc. C, 70.56; H, 7.40; N, 10.29. Found: C, 70.77; H,7.72; N, 10.00.

When ethylene dibromide is used instead of dibromobutane, the productobtained is the 5-(1-azacyclopropyl) indolyl compound.

EXAMPLE 17 J'dethylfl-p-cl1lorobenzoyl-Z-methyl-S- (1 -pyrr0lidin0)3-ind0lyl) acetate In a dry ml. flask is placed 1.2 g. of methyl (2-methyl-5-(1-pyrrolidino)-3-indolyl) acetate in 60 ml. of drydimethylformamide. To this solution, cooled to 0 C., is added 0.23 g. of50% sodium hydride slurry in mineral oil. This mixture is stirred for 30minutes. Then a solution of 0.8 g. of p-chlorobenzoyl chloride dilutedwith 5 ml. of dry dimethylformamide is added dropwise. This reaction isstirred for 4 hours at 0 C. under a nitrogen atmosphere. The reactionmixture is then stirred overnight at room temperature under a nitrogenatmosphere. The reaction mixture is added to an ice waterether mixturecontaining a few milliliters of acetic acid.

The ether layer is separated and the aqueous layer is washed with ether.The combined ether layers are washed once with sodium carbonate andtwice with Water, dried over anhydrous sodium sulfate and evaporated invacuo to an oil. The product is absorbed on 10 g. of silica gel andchromatographed from 60 g. silica gel. The product is collected usingv./v. 1:3 to 1:1 ether-petroleum ether. The combined material iscrystallized from ether, M.P. 6264.

EXAMPLE 18 M ethyl-(1 -p-chlorobenzoyl-Z-methyl-S -nitr0- S-indolyl)acetate In a dried 250 m1. flask is placed 3.9 g. of methyl-(2-methyl-5-nitro-3-indolyl) acetate in 125 ml. dry dimethylformamide. Tothis solution cooled to 0 C. is added 0.8 g. of 50% sodiumhydride-mineral oil. This is stirred under nitrogen for 30 minutes. Tothis is added dropwise 2.75 g. of p-chlorobenzoyl chloride in 15 ml. ofdry dimethylformamide over a 5-minute period. The reaction mixture isstirred 4 hours at 0 C. under nitrogen and then stirred overnight atroom temperature under nitrogen. It is then poured into anice-water-benzene solution containing a few milliliters of acetic acid.The benzene layer is separated and the aqueous layer is washed withbenzene. The combined benzene layers are washed with sodium bicarbonatefollowed by water, dried over anhydrous sodium sulfate and concentratedto dryness in vacuo. The product is crystallized from benzene-Skellysolve B, M.P. 171.

Microanalysis.Calc. C, 59.00; H, 3.91; N, 7.24. Found: C, 59.24; H,4.00; N, 7.39.

The corresponding propionate is formed when an equivalent amount of thecorresponding methyl-ot-(2- methyl-5-nitro-3-indolyl) propionateprepared in Example 13 is used as the starting material.

EXAMPLE 19 Methyl-(1-p-chl0r0benz0yZ-2-methyl-5-dimetl1ylamin0-S-indolyl) acetate To a solution of 0.387 g. ofmethyl-a-(l-p-chl-orobenzoyl-Z-methyl-5-nitro-3-indolyl) acetate in 20ml. of distilled dimethoxyethane is added 1.5 ml. of glacial acetic acidand 0.5 ml. of a 37% solution of aqueous formaldehyde. This mixture isreduced with Raney nickel at 40 p.s.i. and room temperature. After thetheoretical amount of hydrogen has reacted, the reaction mixture isfiltered, concentrated in vacuo to a small volume and diluted withether. The ether solution is Washed with sodium bicarbonate, then withWater, dried with anhydrous sodium sulfate and concentrated in vacuo toan oil.

Micr0analysis.Calcd. C, 65.50; H, 5.50; N, 7.28. Found: C, 65.66; H,5.91; N, 7.46.

EXAMPLE Methyl-(1-p-chlorobenzoyl-Z-methyl-5-acetamin0- 3-ina'0lyl)acetate To 0.388 g. of methyl-(1-p-chlorobenzoyl2-methyl5-nitro-3-indolyl) acetate in ml. of anhydrous ethylacetate is added 0.306g. acetic anhydride. The mixture is reduced with Raney nickel at roomtemperature and p.s.i. After the theoretical amount of hydrogen has beenabsorbed, the catalyst is removed by filtration. The solution isconcentrated in vacuo to a small volume and poured into an iceWater-ether mixture. The ether layer is separated and the aqueous layeris Washed with ether. The combined ether extracts are washed with sodiumbicarbonate followed by water, dried With anhydrous sodium sulfate andconcentrated in vacuo to dryness. The product is crystallized frombenzene and ether, MP. 176-177 C.

Micr0analysis.Calc. C, 63.25; H, 4.80; N, 7.02. Found: C, 63.40; H,4.82; N, 6.89.

EXAMPLE 21 Benzyl-(2-met/iyl-5-nitro-3-ind0lyl) acetate In a dry 250 ml.flask is placed 80 ml. dry benzene and 20 ml. benzyl alcohol. To this isadded 3.0 g. of Z-methyl-5-nitro-3-indolyl acetic acid and 0.2 g. ofp-toluenesulfonic acid. This slurry (which clears on heating) is heatedto reflux under nitrogen. The water formed during the reaction iscollected in a Stark and Dean tube. The reaction is stopped when thedistillate is clear (about 2 hours). The excess benzyl alcohol isremoved in vacuo. The residue is dissolved in benzene and washed withsodium bicarbonate followed by water, dried over anhydrous magnesiumsulfate and concentrated in vacuo. The product is absorbed on 15 g. ofacid washed alumina and chromatographed over 75 g. of acid washedalumina. The product is eluted with v./v. 1:1-3z1 ether-benzene. Theeluate is evaporated and the combined product is crystallized frombenzene-Skellysolve B. M.P. 147-148 C.

Micr0analysis.-Calc. C, 66.66; H, 4.97; N. 8.64. Found: C, 66.83; H,4.77; N, 8.52.

EXAMPLE 22 Benzyl-(I-p-chlorobenzoyZ-Z-methyI-S-nitro-S- indolyl)acetate In a dry 125 ml. flask is placed 3.0 g. of benzyl-(2-methyl-5-nitro-3-indoyl) acetate in ml. of dry dimethylformamide. Tothis solution, cooled to 0 C. in a nitrogen atmosphere is added 0.475 g.of 50% sodium hydridemineral oil. This is stirred for 30 minutes. Then1.65 g. of p-chlorobenzoyl in 10 ml. of dry dimethylformamide is addeddropwise over a 5-minute period. The reaction mixture is stirred at 0 C.for 4 hours under a nitrogen atmosphere followed by stirring at roomtemperature under nitrogen overnight. It is then poured into an icewater-benzene mixture. The benzene layer is separated and the aqueouslayer is washed with benzene. The combined benzene extracts are washedwith sodium bicarbonate followed by water, dried with anhydrous sodiumsulfate and concentrated in vacuo to dryness. The product iscrystallized from benzene-Skellysolve 13 MP. 166167 C.

Micr0analysis.-Calc. C, 64.86; H, 4.14; N, 6.05. Found: C, 64.78; H,4.22; N, 5.91.

EXAMPLE 23 M ethy I-a(1-p-chl 01'0benzoyl-Z-methyl-5-amin0-3 indo/yl)propionate 0.025 M of methyl-ot-(l-p-chlorobenzoyl-Z-methyl-S-nitro-3-indolyl) propionate in 100 ml. of ethanol is hydrogenated in thepresence of 120 mg. of 10% palladium or charcoal catalyst at 40 psi. atroom temperature. After 0.075 M of hydrogen has been consumed, thehydrogenation is stopped, and the solution filtered to remove thecatalyst. The filtrate is concentrated to dryness in vacuo to givemethyl-0M l-p-chlorobenzoyl-2-methyl-5- amino-Z-indolyl) propionate.

EXAMPLE 24 Methyl-a-[]-chl0r0benz0yl-2-met!zyI-5-(N-methylacetamido)-3-ind0lyl] acetateMethyl-l-p-chlorobenzoyl-Z-methyl-S-(N methylacetamido-3-indolyl-acetate is added to a suspension of sodium hydridein dimethylformamide with stirring and ice-cooling. After one hourmethyl iodide is added and the mixture is stirred overnight. Thereaction mixture is poured into iced-water and extracted with ether.Evaporation of the ethereal solution and chromatography of the residualoil on an alumina column, using l525% (v./v.) ether in petroleum etheras the eluent, gives methyl l-p-chlorobenzoyl -2 methyl-S-(N-methylacetamido)-3-indolyl acetate.

EXAMPLE 25 A mixture of 0.02 mole of methyl-a-(l-p-chlorobenzoyl 2methyl-5-amino-3-indolyl)propionate, 0.044 mole of ethylene oxide and0.03 mole of acetic acid in 300 ml. dimethoxyethane is heated to 100 for18 hours in an autoclave. The mixture is then diluted With Water andfiltered to yield crude methyl-[l-p-chlorobenzoyl-Z- methyl 5bis(/3-hydroxyethyl)amino 3 indolyl]-propionate.

The product of A is stirred at 0 in pyridine with two mole proportionsof p-toluenesulfonyl chloride until the reaction is substantiallycomplete. The mixture is poured into water and theS-bis(p-toluenesulfonyloxycthyl)amino compounds is isolated. This isdissolved in benzene and one mole proportion of methylamine is added.The mixture is allowed to stand at room temperature for 3 days. Themixture is poured into iced water containing two equivalents of sodiumcarbonate and extracted with ether immediately. Evaporation of the etheryields methyl- [1-p-chl0robenzoyl-Z-methyl-S-(4-methyl-1-piperazinyl)-3-indolyl] acetate.

Either of the above products, when used in the procedure of Example 7,gives the corresponding free acid.

EXAMPLE 26 A solution of tosyl chloride (0.1 mole) in 200 ml. benzene isadded dropwise with stirring to a solution of methyl-w l-p-chlorobenzoyl-Z-methyl-5 -bis(t3-hydroxyethyl)amino-3-indolyl]acetate(0.1 mole) and pyridine (0.3 mole) in 300 ml. benzene at roomtemperature over a period of one hour. The mixture is then heated underreflux for 3 hours, Washed with water, dried over sodium sulfate andevaporated to a syrup. Chromatography of the syrup on an alumina columnusing 30-50% (v./v.) ether in petroleum ether as the eluent givesmethyl-[l-pchlorobenzoyl 2 methyl-5(4-morpholinyl)-3-indolyl] acetate.

The above product, when used in the procedure of Example 7, gives thecorresponding free acid.

EXAMPLE 27 A. 2-methyI-5-cyan0-3-irzd0lyl acetic acid methyl ester Asolution of p-cyano phenylhydrazine (0.1 mole) and levulinic acid (0.1mole) in 200 ml. concentrated hydrochloric acid is heated at for 20minutes and diluted with iced water (400 ml.). The crude product whichseparates is extracted with ether and chromatographed on a silica gelcolumn to give 2-methyl-5-cyano-3-indolyl acetic acid using 20-50%(v./v.) ether and petroleum ether as the eluent.

The methyl ester is prepared by treatment with diazomethane in etheruntil the yellow of diazomethane persists and the mixture is evaporated.

B. Methyl-a-(l-p-chlorobenzoyl-Z-methyl-5-cyan0-3- indlyl)acetateAlkylation of the ester (prepared in Example 26A above) indimethylformamide with sodium hydride and p-chlorobenzoyl chloride, bythe procedure of Example 2, gives methyl-(l p-chlorobenzoyl 2methyl--cyano-3- indolyl) acetate.

C. Methyl-a- (1-p-chl0r0benz0yZ-Z-methyZ-S-aminomethyl- 3-ina0lyl)acetate The S-cyano ester prepared in Example 27B is hydrogenated inethanol in the presence of Raney nickel and 3 moles of anhydrous ammoniaat 2000 p.s.i. at room temperature to give, after filtration of thecatalyst and evaporation of the reaction mixture,methyl-(1-p-ch1orobenzoyl-Zmethyl-S-aminomethyl-3-indolyl)acetate whichcan be recrystallized from aqueous ethanol.

D. Methyl-(1-p-chlorobenzoyl-2-methyl-5-dimethylamilz0methyl-3-ind0lyl)acetate Treatment of the above ot-aminomethyl indole with 2 moles ofmethyl iodide gives the S-dimethylaminomethyl derivative.

When the products of Examples 27C and 27D above are used in theprocedure of Example 7, the corresponding free acids are obtained.

EXAMPLE 28 a-(l-p-methylmercaptobenzoyl-Z-melhyl-S-mctlzoxy- 3-ind0lyl)-butyric acid When the procedure of Examples 1 and 2 are followed usingethyl a-ethyl levulinate in place of ethyl a-methyl levulinate, there isobtained successively ethyl a-(2-methyl- 5-methoxy-3-indolyl)-butyrateand ethyl a-(l-p-methylmercaptobenzoyl-Z-methyl-5-methoxy-3-indolyl)-butyrate. When the latter product is used in the procedure of Ex ample7 the corresponding butyric acid derivative is obtained.

The starting ethyl a-ethyl levulinate is prepared by alkylation of thesodio derivative of ethyl acetoacetate in ethanol with 1 m. of ethyla-bromobutyrate, followed by hydrolysis and decarboxylation. The a-ethyllevulinic acid obtained is reesterified with 2 N ethanolic hydrogenchloride at reflux temperature for 18 hours.

EXAMPLE 29 Ethyl-a-(l -benz0yZ-Z-methyl-5-meth0xy-3-ind0lyl) acrylate500 ml. of dry ether, 36.02 g. of triphenylphosphonium bromide and 94.36ml. of 1.10 N n-butyl lithium are stirred for 1 hour at room temperatureunder nitrogen. 38 g. of ethyl (2-methyl-S-methoxy-3-indolyl) glyoxylatein 260 ml. of benzene and 500 ml. of dry ether are added, and stirringcontinued for 1 hour. The reaction mixture is transferred to a pressureflask and heated in a closed flask at 6570 C. for 5 hours. The liquid ispoured from the pressure flask and the gum trit-urated with 500 ml. of33% benzene in ether. The solutions are combined and Washed with three500 ml. portions of water, dried over sodium sulfate, filtered andconcentrated in vacuo to a syrup. The syrup is slurried in benzene andcharged onto a 200 g. column of activated alumina. Ethyla-(2-metl1yl-5-methoxy-3-indolyl)-acrylate is eluted by washing thecolumn with 30% ether in petroleum ether and removing the elutingsolvents by evaporation.

The procedure of Example 13B is then followed usingp-nitrophenylbenzoate in equivalent quantities in place of thep-nitrophenylisonicotinate, to giveethyl-a-(l-benzoyl-2-methyl-5-methoxy-3-indolyl) -acrylate.

EXAMPLE 30 Ethyl-a- (1-11enzoyl-2-methyl-5-meth0xy-3-ind0lyl)cyclopropyl carboxylate 1.8 g. of ethyla-(1-benzyl-2-methyl-5-methoxy-3- indolyl)-acrylate in 10 ml. of drytetrahydrofuran is added to 4 g. of diiodomethane, 1.25 g. ofzinc-copper couple and 0.2 g. of iodine in 20 ml. of drytetrahydrofuran. The mixture is refluxed under nitrogen with stir ringfor 20 hours. The reaction mixture is then filtered, the filtrate addedto ice Water, and the whole extracted with three 50ml. portions ofether. The combined ether extracts are washed with two SO-ml. portionsof water, dried over sodium sulfate, filtered and concentrated. Thesyrup thus obtained is .poured onto a 60 g. alumina column as a slurryin benzene. Ethyl oc-(lbenzoyl 2 methyl-5-methoxy-3-indolyl)cyclopropylcarboxylate is collected from the column by elution with 60%ether-petroleum ether.

EXAMPLE 31 The corresponding N-l aroyl or heteroaroyl derivatives ofbenzyl a (2-methyl-5-methoxy-3-indolyl)propionate,benzyl-(2-methyl-5-methoxy-3-indolyl) acetate and benzyl-(Z-methyl-S-nitro-3-indolyl) acetate are obtained by reacting theseesters by the procedure of Example 13B with the p-nitrophenyl esters ofthe following acids, the p-nitrophenyl esters having been obtained fromthe acids by the procedure of Example 13A, using in each case theequivalent amount of the selected acid in place of the isonicotinic acidused in 13A and of its nitrophenyl ester used in 13B and equivalentquantities of the indolyl esters: l-methylpyrryl-2-carboxylic acid,5-methylapyrazole-3 carboxylic acid,l,5-dimethyl-4-bromopyrazole-3-carboxylic acid, 1-phenylpyrazole-4-carboxylic acid, l-phenyl-S-pyrazolone- 3-carboxylicacid, 2-phenyl-5-methloxazole-4-carboxylic acid, isoxazole-3carboxylicacid, 5-phenylisoxazole-3-carboxylic acid,1,2-benzoisothiazole-3-carboxylic acid, 1,2,3- thiadiazole-4-carboxylicacid, 1-methyl-1,2,3-triazole-4- carboxylic acid, nicotinic acid,picolinic acid, isonicotinic acid-N-oxide, 3-chloroisonicotinic acid,6-methoxynicotinic acid, 6-phenylnicotinic acid, u-pyrone-5-carboxylicacid, pyridazine-4-carboxylic acid, 3-keto-4-methyl-2-phenyl-2,3-dihydropyridazine-6-carboxylic acid, cinnoline-4-carboxylic acid,Z-methylmercapto-4-chloropyrimidine-S-carboxylic acid,2,4-dichloropyrimidine-5-carboxylic acid, pyrazinoic acid,S-methoxypyrazinoic acid, p-difluoromethoxy benzoic acid (prepared bythe action of difluorochloromethane on the p-hydroxybenzoate of benzylalcohol followed byhydrogenation of the benzyl group). The esters soobtained are converted to the free acids by the procedure of Example 7C.

EXAMPLE 32 Ethyl-ot-(l-p-clzlorobenzoyl-Z-methyl-5-eth0xy-3-indolyl)propionate The procedure of Example 1A is followed using an equivalentquantity of p-ethoxyphenylhydrazine hydrochloride in place of themethoxyphenylhydrazine to give ethyl-a- 2-methyl-5-ethoxy-3 -indolylpropionate. When this is used in the procedure of Example 3 there isobtained ethyl on(1-p-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl)propionate. Thisproduct, when used in the procedure of Example 7, yields thecorresponding free a-indolyl propionic acid.

Similarly, when p-propoxy and p-butoxy phenylhydrazine are used in theabove procedures, the correspondingly S-Substituted indolyl acids areobtained.

When the procedure of Example 1A is followed using in place of thep-methoxyp-henylhydrazine, equivalent amounts of p-ethylphenylhydrazine, p-butylphenylhydrazine and p-fluorophenylhydrazine (eachobtainable by diazotization of the corresponding p-substituted anilineand reduction of the diazo) and the resultant indolyl ester is acylatedby the procedure of Example 3 and further treated by the procedure ofExample 7, the corresponding 5-substituted indolyl esters and acids areobtained.

When the procedure of Examples 1A, 3 and 7 are followed starting withphenylhydrazine, the corresponding S-unsubstituted indolyl esters andacid are produced.

EXAMPLE 3 3 I -benzy I-Z-methy l--m ethoxy-S-indoly I-acetam'ide To asuspension of 1.0 g. of 50% sodium hydride in 80 ml. benzene is added4.4 g. of 2-methyl-5-methoxy-3- indolylacetamide with stirring. Twentyml. of dimethylformamide is then added, followed by 2.8 g. benzoylchloride twenty minutes later. The reaction mixture is stirred at roomtemperature for 1 hour and then poured into 400 ml. of ice and water.The precipitate is collected on a filter, M.P. 215-218". The crudeproduct is recrystallized from ethyl acetate twice, M.P. 219-220. Itsultra violet absorption spectrum in ethanol shows maxi ma at x 2675 A.,E 406 and )t 3160 A., E 188.

Micr0arzalysis.-Calc. for C H N O C, 71.24; H, 5.03. Found: C, 71.00; H,5.35.

EXAMPLE 34 1-benz0yl-2-methyl-5-methoxy-3-ind0lyl-acetic acid To asolution of 3.2 g. of 1-benzoyl-2-methy1-5-methoxy-3-indolyl acetamidein 50 ml. dimethoxyethane containing 1 ml. of 12 N hydrochloric acid at0 is added 0.7 g. of sodium nitrite with stirring. After gas evolutionhas subsided the mixture is poured into 200 ml. of iced water and theprecipitate is extracted with methylene chloride. The methylene chloridesolution is extracted with sodium bicarbonate solution. Acidification ofthe aqueous solution with 2 N hydrochloric acid precipitates the desiredacid which is purified by recrystallization from benzene and from ethylacetate-Skellysolve B.

EXAMPLE 35 The acylation procedures of Example 3 or of Example 12A arefollowed using various aromatic acyl chlorides in equivalent quantitiesin place of p-chlorobenzoyl chloride and using, as necessary, esters of2-methyl-5-methoxy- 3-indolyl acetic acid or ofa-(2-methyl-5-methoxy-3-indolyl)propionic acid. Some of the resultingesters are converted to the corresponding free acid by the method ofExample 7 or of 12B as indicated below. Where the method of Example 12Bis used, the l-acylation is by the process of Example 12A. The productsobtained by these experiments are: (1p-methoxybenzoyl-2-methyl-5-methoxy-3-indolyl)acetic acid M.P. 8889 C.(free acid by method of Example 7), a (l-p-methoxybenzoyl-Z-methyl-5-methoxy-3-indolyl)propionic acid M.P. 65 C. (free acid bymethod of Example 7),methyl-(l-p-bromobenzoyl-Z-met-hyl-S-methoxy-3-indolyl) acetate M.P.106- 107.5 C., methyl-(1-p-nitrobenzoyl-2-methyl-5-methoxyl- 3-indolyl)acetate M.P. 130132 C.,methyl-(l-o-chlorobenzoyl-2-methyl-5-methoxy-3-indolyl) acetate M.P. 91-93 C., methyl-(1-m-chlorobenzoyl-Z-methyl-5-methoxy- 3-indolyl) acetateM.P. 5152 C., methyl-(l-p-phenylbenzoyl-2methyl-S-methoxy 3 indolyl)acetate M.P. 101.5103 C., methyl-(l-p-aoetoxybenzoyl-Z-methyl-5-methoxy-3-indolyl) acetate M.P. 99101 C., ethyl-[1- (4 thiazolylcarboxy)2 methyl-5-methoxy-3-indolyl] acetate M.P. 7682 C.,ethyl[1-(2-thenoyl)-2-methyl-5- methoxy-3-indolyl]acetate (oil),lZ-bU'tYl-oc-(l p hromobenzoyl 2-methyl-5-methoxy-3-indolyl)propionateM.P. 103-105 C., methyl-(1-ot-naphthoyl-2-methyl-5-methoxy-3-indolyl)acetate (oil), methyl-(1-p-benzyloxybenzoyl-2- methyl 5methoxy 3 indolyl) acetate M.P. 1l6118 0, methyl (1 p hydroxybenzoyl 2methyl 5- methoxy 3 indolyl)acetate M.P. 155l58 C. (prepared from thep-benzyloxybenzoyl compound by catalytic hydrogenation over palladium),methyl (1 obenzyloxybenzoyl-2-methyl-5-methoxy-3 indolyl)acetate (notisolated-used to prepare next compound by catalytic hydrogenation overpalladium), methyl-(l-o-hydroxybenzoyl-2-methyl-5-methoxy-3-indolyl)acetate (oil), methyl- (1 o-fluorobenzoyl-2-methyl-5-methoxy-3-indolyl)acetate M.P. 9899 C., [1-(2-thenoyl)-2 methyl-5-methoxy-3- indolyl]acetic acid M.P. 62 C. (method of Example 12), methyl(1-/3-naphthoyl-2-rnethyl-5-methoxy-3-indolyl)acetate M.P. 120124 C.,methyl-[l-(5-chloro-2-thenoyl -2-methyl-5-methoxy-3-indolyl] acetate(oil), (l-p-trifluoromethylbenzoyl-Z-methyl-5-indolyl)acetic acid M.P.16 9171 C. (method of Example 12), methyl [1-(2,6-dimethoxybenzoyl)-2-methyl-5-methoxy-3-indolyl] acetate M.P. 139.5141C., methyl [1-(o-p-dichlorobenzoyl)-2- methyl-5-methoxy-3-indolyl]acetate (oil).

EXAMPLE 36 The procedure of Example 1A is followed using an equivalentquantity of each of the following phenylhydrazines in place of thep-methoxyphenyl hydrazines: mchlorophenylhydrazine,m-mcthoxyphenylhydrazine, p-fiuorophenylhydrazine.

When the resulting indolyl acid is acylated by the procedure of Example3, the corresponding l-chlorobenzoyl indolyl acids are obtained.

EXAMPLE 37 Methyl-5-meth0xy-3-indolylacetate is reduced at 4000 psi. ofhydrogen over nickel catalyst at room temperature. The resultantmethyl-5-methoxy-2,3-dihydro-3-indolyl acetate is acylated by theprocedure of Example 3 to give methyl-(1-p-chlorobenzoyl-5-methoxy-2,3-dihydro- 3-indolyl)acetate. When this is stirredat room temperature in 100 times its weight of a 0.1 N solution ofsodium hydroxide in 95% ethanol, the corresponding free acid isobtained.

EXAMPLE 38 1-p-chlorobenzoyZ-Z-methyl-5-meth0xy-2,3-dihydr0-3- indolylacetic acid A mixture of 3 g. of 10% palladium on charcoal in ml. ofglacial acetic acid is treated in a glass-lined bomb with hydrogen gasuntil the hydrogen uptake ceases. At this time 0.015 mole of1-p-chlorobenzoyl-2-methyl-S- methoxy-3-indolyl-acetic acid is added andthe temperature is raised to C.

The reaction is stopped when the theoretical hydrogen uptake is reached,the mixture filtered, and the solvent removed in vacuo leaving a clearoil that solidifies on standing or on trituration with benzene.Fractional crystallization from benzene-petroleum ether removes amixture of product and de-chlorinated product from unchanged startingmaterial. Esterification with diazomethane of the reduced mixture andchromatography of the crude ester mixture on g. of acid-washed aluminausing ether-petroleum ether (v./v. 20100%) as eluent gives the methylester of the product.

The ester is then dissolved in 60 ml. of methanol. An equimolar amountof sodium hydroxide in 5 ml. of water is added, and the resultantmixture stirred under nitrogen overnight. Excess water is then added,the solution filtered and washed with ether, made acidic with chloro--form. The chloroform solution is washed with water, dried over anhydroussodium sulfate, and concentrated in vacuo to give1-p-chlorobenzoyl-2-methyl-5-methoxy- 2,3-dihydro-3-indolylacetic acid.

When any of the other indole acids shown in Examples 1, 3, 5, 6, 7, 8,9, 10, 12, 16, 17, 19, 20,23, 24, 25, 26, 27C, 27D, 30, 32, 33 and 36are used in this procedure, the corresponding indoline is obtained.

2.1 EXAMPLE 39 1-p-triflu0r0methylbenzoyl-2-methyl-5-meth0xy-2,3-dihydr-3-ind0lylacetic acid Using the conditions set forth in Example38, l-p-trifluoromethylbenzoyl 2 methyl-5-methoxy-3-indolylacetic acid(0.015 mole) is reduced and the crude reduction mixture obtained isesterified with diazomethane. Chromatography of the crude esterificationmixture on 150 g. of acid-washed alumina using ether-petroleum ether(v./v. 100%) as eluent gives the methyl ester of the product.

The ester is then dissolved in 60 ml. of methanol and an equimolaramount of sodium hydroxide in 5 ml. of Water is added, and the resultantmixture stirred under nitrogen overnight. Excess water is then added,the solu tion filtered and washed with ether, made acidic with 2.5 Nhydrochloric acid and extracted with chloroform. The chloroform solutionis Washed with water, dried over anhydrous sodium sulfate, andconcentrated in vacuo to give 1 ptrifluoromethylbenzoyl-Z-methyl-S-methoxy- 2,3-dihydro-3-indolylaceticacid.

EXAMPLE 40 Methyl ,8-(3-ind0linyl)-pr0pionate hydrochloride A. MethylB-(3-ind0lyl)-pr0pi0nate.A solution of ,B-3-indoly1 propionic acid(0.132 mole) in 180 ml. of a 3% concentrated sulfuric acid-anhydrousmethanol mix ture is refluxed under nitrogen for three hours. Afterremoval of the excess methanol in vacuo, 400 ml. of ether is added, andthe ether solution washed with water, saturated sodium bicarbonatesolution, water until neutral, and then dried over anhydrous sodiumsulfate. The ether solution is then filtered, concentrated in vacuo toca.

200 ml., and 400 ml. hexane added. After precipitation is complete, themixture is filtered, the white crystals rinsed with petroleum ether andfinally air dried to give an 84% yield of methylfl-(3-indolyl)-propionate, M.P. 7880 C.

B. Methyl ,8-(3-ind0linyl)-pr0pi0nate hydr0chl0ride. A solution ofmethyl fi-(3-indolyl)-propionate (0.116 mole) in 150 ml. methanol ishydrogenated in the presence of g. of Raney nickel at room temperaturefor 48 hours under a hydrogen atmosphere of 3150 p.s.i.

The mixture is then filtered, concentrated in vacuo to ca. 50 ml., andadded to 100 ml. anhydrous ether. To this ether solution is then added200 ml. of a saturated anhydrous hydrogen chloride-ether solution, andthe oily hydrochloride precipitates. The volume of the mixture is thenadjusted to 500 ml., and stirred in an ice bath until the oil thickens.The ether solution is then decanted from the oil, an equal volume offresh ether added, and the cooling and stirring repeated untilsolidification takes place. The mixture is then filtered, the light-pinkto white solid rinsed with ether and then dried in vacuo to give methyl(3-(3-indolinyl)-propionate hydrochloride.

EXAMPLE 41 ,8- (1-p-chlorobenzoyl-Z,3-dihydr0-3-ind0lyl) propionic acidA dry 50 ml. flask under a nitrogen atmosphere is charged with methyl,B-(B-indolinyl)-propionate hydrochloride (0.008 mole) in 20 ml. of drypyridine. The mixture is then cooled in an ice-water bath, andp-chlorobenzoyl chloride (0.009 mole) added with stirring. The mixture,containing precipitated pyridine hydrochloride, is then stirred for onehour. At this time, ca. 100 ml. of water is added to this mixture andthe mixture extracted with ca. 100 ml. of ether. The ether layer is thenwashed with equal volumes of water, 2.5 N hydrochloric acid, Water,saturated sodium bicarbonate solution, and finally water, and dried overanhydrous sodium sulfate. After filtering, the ether is removed in vacuoto give the methyl ester of the product. This is taken up in ml. ofmethanol and treated with sodium hydroxide (0.008 mole) in 2.5 ml. ofwater at room temperature, overnight under a nitrogen atmosphere. To thesolution is then added 150 ml. of water, and the basic aqueous solutionextracted with 2 x 150 ml. of ether. The aqueous layer is then madeacidic with 2.5 N hydrochloric acid, extracted with 2 x 150 ml. ofether, and the ether layer washed with 2 x 15 0 ml. of water and driedover anhydrous sodium sulfate. Filtering and concentration in vacuo ofthe ether solution gives B-(1-p-chlorobenzoyl-2,3-dihydro-3-indolyl)-propionic acid, M.P. l26127.5 C. after recrystallization frombenzene-petroleum ether.

EXAMPLE 42 B- (1-p-methylbenzoyl-2,3-dihydr0-3-ind0lyl) propionic acidFollowing the acylation and saponification procedures set forth inExample 41, but using p-methylbenzoyl chloride in place ofp-chlorobenzoyl chloride there is obtained 6 (1 p methylbenzoyl 2,3dihydro 3 indo1y1)- propionic acid, M.P. 139140 C. Methyl ester: M.P.93.5-96 C.

EXAMPLE 43 Following the identical acylation and saponificationprocedures set forth in Example 41, but replacing the p-chlorobenzoylchloride with m-methylbenzoyl chloride, o-methoxybenzoyl chloride,m-methoxybenzoylchloride, p-methoxybenzoylchloride,o-chlorobenzoylchloride, m-chlorobenzoylchloride,p-trifiuoromethylbenzoylchloride, o-fluorobenzoylchloride,m-fluorobenzoylchloride, p-fluorobenzoylchloride, p-methylthiobenzoylchloride, cinnamoyl chloride, o,p-dichlorobenzoyl chloride, a-thenoylchloride, nicotinoyl chloride, phenyl chloroformate,thiazole-4-carboxylic acid chloride, 3-furoyl chloride,1-methylimidazole-5-carboxylic acid chloride,1,3-dimethyl-2,3-dihydro-2-oxoi1nidazole-4-carboxylic acid chloride,

S-fluoro-Z-thenoyl chloride,

3-thenoyl chloride,

5 -nitro-2-furoylchloride, 1-methylindazole-3-carboxy chloride,1-methyl-6-nitroimidazole-3-carboxy chloride, oxaZole-4-carboxychloride, benzoxazole-Z-carboxy chloride, thiazole-4-carboxy chloride,thiazole-2-carboxy chloride, 2-phenylthiazole-4-carboxy chloride,Z-benzylmercaptothiazole-4-carboxy chloride, p-cyanobenzoyl chloride,p-trifiuoromethylthiobenzoyl chloride, p-rnethylsulfinylbenzoylchloride, p-methylsulfonylbenzoyl chloride, p-benzylthiobenzoylchloride, pmercaptobenzoy1 chloride, and p-nitrobenzoyl chloride,

there is obtained, respectively, 5-(1-m-methylbenzoyl-2,3-dihydro-3-indolyl) -propionic acid, M.P. 132 C.;B-(1-o-methoxybenzoyl-2,3-dihydro-3 -indolyl propionic acid;

;3'-( 1-m-methoxy-benzoyl-2,3-dihydro-3 -indolyl propionic acid, M.P.149l5l C.; fl-(1-p-methoxybenzoyl-2,3-dihydro-3-indolyl)- propionicacid, M.P. 147-149 C ,8-(1-o-chlorobenzoyl-2,3-dihydro-3-indolyl)-propionic acid;

,8-(1-m-chlorobenzoyl-2,3-dihydro-3-indolyl)-propionic acid, M.P.120-121 C.;

[H l-p-trifluoromethylbenzoyl-Z,3-dihydro-3-indolyl) propionic acid;

B( l--flu0robenzoyl-2,3-dihydro-3-indolyl)propionic acid, M.P. 9S100 C.;

,6-(1-m-fiuorobenZoyl-2,3-dihydro-3-indolyl)propionic acid, M.P. 147-148(3.;

,B-( l-p-fluorobenzoyl-2,3-dihydro-3-indolyl) propionic acid, M.P.143-l44 C.;

[3- l-p-methylthiobenzoyl-2,3-dihydro-3-indolyl) propionic acid;

fl-(1-cinnamoyl-2,3-dihydro-3-indolyl)propionic acid,

M.P. 164165 C.;

/3-(1-o,p-dichlorobenZoyl-2,3-dihydro-3-indolyl) propionic acid;

fl-(1-a-thenoyl-2,3-dihydro-3-indolyl)propionic acid,

M.P. 154.5-155 C.;

fl- 1-nicotinoyl-2,3-dihydro-3-indolyl) propionic acid,

;3-(1-phenoxycarbonyl-2,3-dihydro-3-ind0lyl) propionic acid,

B-(1-4-thiazolylcarbonyl-2,3 -dihydro-3 -indolyl) propionic acid,

fl-[1-(3-furoyl)-2,3-dihydro-3-indolyl]propionic acid,

B-[ 1-( 1-methylimiazole-5-carboxy -2,3-dihydro-3- indolyl1propionicacid,

B-[1-1,3-dimethyl-2,3-dihydro-2-oxoimidazole-4-carboxy)-2,3-dihydro-3-indolyl] propionic acid,

fl-[1-(5-fluoro-2-thenoyl)-2,3-dihydro-3-indolyl] propionic acid,

fl-[1-(3-thenoyl)-2,3-dihydro-3-indolyl]propionic acid,

/3-[1-(5-nitro-2-fur0yl)-2,3-dihydro-3-indolyl] propionic acid,

,8- 1- 1-methylimidazole-3-carboxy)-2,3-dihydro-3- indolyl]propionicacid,

{3-[1-( 1-methyl-6-nitroindazole-3-carb oxy)2,3-

dihydro-3-indolyl]propionic acid,

fi-[ l-(oxazole-4-carboxy) -2,3-dihydro-3-indolyl] propionic acid,

,8-[ l- (benzoxazole-Z-carboxy) -2,3-dihydro-3-indolyl] propionic acid,

,8-[1-(thiazole-4-carboxy)-2,3-dihydro-3-indolyl] propionic acid,

/3-[1-(thiazole-2-carboxy)-2,3-dihydro-3-indolyl] propionic acid,

5-[ l- (2-phenylthiazole-4-carboxy) -2,3-dihydro-3- indolylJpropionicacid,

(3-( l-p-cyanobenZoyl-2,3-dihydr0-3-indolyl) propionic acid,

fl-( 1-p-trifiuoromethylthiobenzoyl-Z, 3-dihydro-3-indolyl) propionicacid,

5-( 1-p-methylsulfinylbenzyl-Z, 3 -dihy dro-3-indolyl) propionic acid,

fl-( l-p benzylthiobenzoyl-2,3-dihydro-3-indolyl) propionic acid,

,8-( l-p-mercaptobenzoyl-Z, 3 -dihydro-3-indolyl) propionic acid, and

fll-p-nitrobenZoyl-2,3-dihydro-3-indolyl)propionic acid.

EXAMPLE 44 [3 (1 N phenylcarbamyl 2,3 dihydro -3 indolyl) propionic acidTo a solution of methyl {3-(3-indolinyl)propionate (0.005 mole) in 5 ml.of anhydrous benzene is added phenylisocyanate (0.005 mole) in 5 ml.benzene. After a slight exothermic reaction has subsided, the mixture isstirred under nitrogen for 1 hour, at which time the benzene is removedin vacuo. The resultant oil is then chromatographed on a 60 g. silicagel column using etherpetroleum ether (v./v. 5-50%) as eluent. The esterobtained, M.P. 778l C., is then saponified with an equimolaraqueous-methanol sodium hydroxide solution as in 24 Example 41 to give;3-(l-N-phenylcarbamyl-Zfi-dihydro- 3-indolyl) propionic acid.

EXAMPLE 45 Methyl -(3-ind0linyl)ot-methylpropionate[3-3-indolinyl-e-methylpropionic acid, M.P. 117l21 (3., is preparedfollowing the proceduce for fi-El-indolylpropionic acid. Following theesterification procedure of Example 41A is then obtained oily methylfi-3-indolinyl propionate in Example 4013. After removal of the solventin vacuo, the residue is dissolved in ca. 250 ml. of ether and extractedwith 2 x 200 ml. hydrochloric acid. The aqueous solution is then washedwith 2 x 200 ml. ether, made slightly basic With concentrated ammoniumhydroxide, and extracted with 2 x 200 ml. ether. The ether solution isthen washed with 2 x ml. water, dried over anhydrous potassiumcarbonate, filtered, and concentrated in vacuo to give methyl{3-(3-indolinyl)amethylpropionate.

EXAMPLE 46 B (1 p chlorobenzoyl 2,3 dihydro 3 indolyl) amethylpropionicacid Following the complete acylation and saponification procedures setforth in Example 41, but using methyl 5 3 indolinyl 0t methylpropionateinstead of methyl t3-3-indolinylpropionate there is obtained,B-(l-p-chlorobenzoyl-Z,3-dihydro-3-indolyl) ot-methylpropionic acid.

Similarly, [3 (1 benzoyl 2,3 dihydro 3 indolyl) xmethyl propionic acidis obtained using benzoyl chloride in place of p-chlorobenzoyl chloridein the above acylation.

EXAMPLE 47 Ethyl ,8-(3-indoliiiyl)B-methylpropionate Ethyl[M3-indolyl)e-methylpropionate is prepared via the published procedurefor the corresponding 5,6-dimethoxy analog using, however, Raney nickelin place of the 10% palladium on carbon catalyst.

The reduction is then concentrated in vacuo to a gel like substancewhich on trituration with ether partially crystallizes. After filteringand rinsing the solid material with ether, the filtrate and rinsings areconcentrated in vacuo to a red oil. Chromatography of the oil on an acidwashed alumina column (Wt/Wt. 1:30) with benzene as eluent gives ethylfl-(3-indolyl)fi-methylpropionate.

Reduction and worloup of reduction mixture is carried out as for thetit-methyl analog (Example 45) gives ethyl ,8- 3 -indolinyl)B-methylpropionate.

EXAMPLE 48 Following the complete acylation and saponificationprocedures set forth in Example 41, but using ethyl ,8-3- indolinylfi-methylpropionate in place of methyl B-3-indolinyl propionate there isobtained B-(l-p-chlorobenzoyl-Z,3-dihydro-3-indolyl)B-methylpropionicacid.

Similarly, 8-(1-ben2oyl-2,3-dihydro-3-indolyl)[i-methylpropionic acid isobtained using benzoyl chloride in place of p-chlorobenzoyl chloride inthe above acylation.

EXAMPLE 49 Methyl -(3-ind0linyl)bitty/ate Methyl -3-indolylbutyrate isprepared from 'y-3-indolylbutyric acid following the procedure used formethyl-[3-B-indolylpropionate in Example 40A. Reduction and purificationas set forth in Example 45 for methyl B-(3-indolinyl)a-methylpropionategives methyl 7- 3 -indolinyl) butyrate.

25 EXAMPLE s Following the complete acylation and saponificationprocedures set forth in Example 41, but using methyl'y-(3-indolinyl)-butyrate in place of methyl ,B-3-indolinylpropionategives 'y-(l-p-chlorobenzoyl-2,3-dihydro-3-indolyl)-butyric acidf EXAMPLE51 1-p-chl0robenz0yl-2,3-dihydr0-3-ind0lylacetic acid 3-indolylaceticacid is reduced and the resultant indoline reacted with p-chlorobenzoylchloride via a Schotten- Baumann type acylation according to aliterature procedure to give1-p-chlorobenzoyl-2,3-dihydro-3-indolyl-acetic acid, M.P. 178 C. (fromethanol).

EXAMPLE 2 1-p-chlorobenzoyl-2,3-dimethyl-2,3-dihydr0-3-ind0lylaceticacid Following the procedures set forth in Example 41, ethyl2,3-dimethyl-3-indolinyl-acetate is reacted with pchlorobenzoyl chlorideand the resultant compound saponified to give1-p-chlorobenzoyl-2,3-dimethyl-2,3-dihydro- 3-indolylacetic acid.

EXAMPLE 53 Methyl B-(S-methoxy-S-indolinyl) -pr0pionate A solution ofmethyl fi-(5-methoxy-3-indolyl)-propionate (0.01 mole) in 25 ml.methanol is reduced under a hydrogen pressure of 23503200 psi. at 100 C.in the presence of 3 g. of Raney nickel catalyst for 24 hours. Thereduction mixture is filtered and concentrated in vacuo to an oil. Theoil is dissolved in 200 ml. ether and the ether solution filtered andextracted with 2 x 200 ml. 2.5 N hydrochloric acid. The aqueous layer iswashed with 2 x 200 ml. ether, made slightly alkaline with concentratedammonium hydroxide, and extracted with 2 x 200 ml. ether. The etherlayer is Washed with 200 ml. portions of water until neutral to litmuspaper, and dried over anhydrous potassium carbonate. Filtering andconcentration in vacuo of the ether solution gives methyl,8-(5-methoxy-3-indolinyl)propionate.

EXAMPLE 54 f3-(1-p-chlorobenzoyl-S-methoxy-Z,3-dihydr0-3-ind0lyl)-propionic acid Following the complete acylation and saponificationprocedures set forth in Example 41, but using methyl8-(5-methoxy-3-indolinyl)-propionate in place of methyl5-3-indolinyl-propionate there is obtainedB-(l-p-chlorobenzoyl-S-methoxy-Z,3-dihydro-3-indolyl)-propionic acid.

Similarly, ,8- l-benzoyl-S -methoxy-2,3 -clihydro-3-indolyl propionicacid, M.P. l79.5-l81.5 C., is obtained using benzoyl chloride in placeof p-chlorobenzoyl chloride in the above acylation.

EXAMPLE 55 fl- (1-p-chl0r0benz0yl-6-meth0xy-2,3-dihydr0-3-ind0lyl)propionic acid Following the procedures used for the 5-methoxy analog(Examples 53 and 54), methyl ,8-(6-methoxy-3-indolyl)- propionate isreduced, and the indoline derivative p-chlorobenzoylated and saponifiedto give ,B-(l-p-chlorobenzoyl 6 methoxy 2,3 dihydro 3 indolyl)-propionic acid.

EXAMPLE 56 ,B- 1 -p-chl0r0 benz0yl-5,6-dimethoxy-Zfi-dihydr0-3-indolyl)-propionic acid Following the procedures used for themonomethoxy analog (Examples 53 and 54), methyl ,8-(5,6-dimethoxy-3-indolyl)-propionate is reduced and the indoline derivativep-chlorobenzoylated and saponified to give ,B-(I-pchlorobenzoyl 5,6dimethoxy 2,3 dihydro 3 indolyl)-propionic acid.

EXAMPLE 57 A dried 1 1. three neck flask equipped with a droppingfunnel, mechanical stirrer and nitrogen inlet tube is charged with 170ml. of anhydrous methanol, 0.17 mole anhydrous sodium acetate and 0.14mole p-tolylhydrazine hydrochloride. The mixture is stirred undernitrogen for one half hour. 'y-Formylbutyrate (0.16 mole) is added inone portion, and a slight exothermic reaction occurs. The mixture isaged for two hours. A solution of 21 g. of anhydrous hydrogen chloridein ml. of anhydrous methanol is then added over twenty minutes, and themixture gently refluxed under nitrogen for two and a quarter hours.After cooling, the mixture is filtered and the filtrate and methanolrinsings concentrated in vacuo to dryness. The residue is then taken upin 1 l. of ether, filtered, concentrated in vacuo to dryness, andpartitioned between ca. 700 ml. chloroform and an equal volume of 2.5 Nhydrochloric acid. The chloroform layer is then washed with anotherportion of dilute acid, then with an equal volume of saturated sodiumbicarbonate solution, and finally with equal volumes of water untilneutral. After drying over anhydrous potassium carbonate, the chloroformsolution is concentrated to a small volume, charged into a 500 g. acidwashed alumina column and eluted with ether to give methylfi-(5-methyl-3-indolyl)- propionate.

EXAMPLE 5 8 ,B(Z-p-chlorobenzoyl-5-methyl-2,3-dihydro-3-ind0lyl)propionic acid Following the procedures used for the 5-hydrogen-amethylanalog (Examples 45, 40B and 46), methyl ,8-(5-methyl-3-indolyl)-propionate is reduced, and the indoline derivativepurified, p-chlorobenzoylated and saponified to giveB-(l-p-chlorobenzoyl 5 methyl-2,3-dihydro-3- indolyl) -propionic acid.

EXAMPLE 59 Methyl 5- (5 -flu0r0-3-ind0lyl -propi0nate Following theprocedure used in Example 57 for the S-methyl analog but usingp-fluorophenylhydrazine hydrochloride in place ofp-methylphenylhydrazine hydrochloride, there is obtained methyl[3-(5-fluoro-3-indolyl)- propionate.

EXAMPLE 60 Following the procedures used for the S-hydrogen-amethylanalog (Examples 8(3B) and 9), methyl fi-(S-fluoro-3-indolyl)-propionate is reduced, and the indoline derivativepurified, p-chlorobenzoylated and saponified to give,lfl-(l-p-chlorobenzoyl 5 fluoro-2,3-dihydro-3- indolyl)-propionic acid,

EXAMPLE 61 Methyl [i- (1 -p-ch lorobcnzoy l-5-nitr0-2,S-dihydro-S-indolyl) -pr0pi0nate Nitration of methylfl-(1-p-chlorobenzoyl-2,3-dihydro- 3-indolyl)-propionate according topublished procedures for N-benzoyl-S-nitroindoline andN-acetyl-S-nitroindoline, followed by chromatography on an acid-washedalumina column (wt./wt. 1:30) using ether-petroleum ether (v./v.20-100%) gives methylfi-(l-p-chlorobenzoyl-5-nitro-2,3-dihydro-3-indolylpropionate.

EXAMPLE 62 fl-(1-p-chlorobenzoyl-S-dimethy[amino-2,3-dihydr0-3-indolyl)-propionic acid A. B-(Lp-chlorobenzoyl 5nitr0-2,3-dihydr0-3-ind0- chlorobenzoyl 5nitro-2,3-dihydro-3-indolyl)-propionate using the procedure in Example41 gives fl(1-pchlorobenzoyl-2,3-dihydro 5 nitro-3-indolyl)-propionicacid.

B. fl-(I-p-chlorobenzoyl 5 dimethylamin-2,3-dihydr0-3-ind0lyl)propionicacid-A solution of fl-(l-pchlorobenzoylnitro-2,3-dihydro-3-indolyl)-propionic acid in 8 ml. of1,2-dimethoxyethane, 0.5 ml. of glacial acetic acid and 0.5 ml. of 37%aqueous formaldehyde is reduced in the presence of platinum oxide atroom temperature under a hydrogen pressure of 40 p.s.i. After filteringand removal of the solvent in vacuo the residue is spotted on several 8X 8 thin-layer chromatography plates coated with Brinkman Silica-gel Gand eluted ascendingly with a methanol-ethyl acetate solvent system togivefl-(1-p-ehorobenzoyl-S-dimethylamino-2,3-dihydro-3-indolyl)-propionicacid.

EXAMPLE 63 fl-(J-p-chlorobenzoyl-S-hydroxy-Z,3-dihydr0-3-indolyl)-propionic acid A. Methyl fi-(l-p-chloroben zoyl 5hydr0xy-2,3-dihydr0-3-ind0lyl)-pr0pi0nate.Methylfi-(Lp-chlorobenzoyl-5-methoxy-2,3-dihydro-3-indolyl) -propionate (0.001m.) is added slowly to excess pyridine hydrochloride at 160220 C. Aftercooling, the mixture is partitioned between 500 ml. water and an equalvolume of chloroform. The chloroform layer is Washed with 2 x 150 ml.

of 2.5 N hydrochloric acid, 150 ml. portions of water Methyl2-phenyl-3-indolylacetate A dry 1 l. three-necked flask equipped with athermometer, dropping funnel, mechanical stirrer and nitrogen inlet tubeis charged with 150 ml. of anhydrous methanol and 0.145 mole ofanhydrous sodium acetate. Phenylhydrazine hydrochloride (0.125 mole) isthen added and the mixture aged thirty minutes under nitrogen. At thistime 3-benzoylpropionic acid (0.142 mole) in 80 ml. of anhydrousmethanol is added all at once and the mixture stirred for one half hour.Anhydrous hydrogen chloride (18 g.) in 125 ml. of anhydrous methanol isadded over a period of twenty minutes, and the resultant mixture heatedat a gentle reflux for two hours. After cooling, ca. 500 ml. of benzeneis added, the mixture filtered, the residue rinsed with 5 00 ml.benzene, and the combined benzene solutions washed with 3 x 200 ml. 2.5N hydrochloric acid, 200 ml. water, 3 x 200 ml. saturated sodiumbicarbonate solution, 200 ml. portions of water until the washings areneutral, and the benzene layer dried over sodium sulfate anhydrous.After filtering and concentration in vacuo to a small volume the benzenesolution is charged onto a 500 g. acid-washed alumina column and elutedwith ether-petroluem ether (v./v. -50%) to give methyl2-phenyl-3-indolyl acetate. The corresponding acid (M.P. 173-175 C.) isob tained by saponification.

28 EXAMPLE 65 I-p-chlorobenzoyl-Z-phenyl-2,3-dihydr0-3-ind0lyl aceticacid A. Methyl Z-phenyl 3 indolinylacetate.Methyl 2-phenyl-3-indolylacetate is reduced to the above indoline derivativeusing the published procedure for 2,3-dimethyl and 2,3-diphenylindoline.

B. J-p-chlorobenzoyl 2 phanyl-2,3-diltydro-3-ind0- lyl-aceticacid.-Following the complete acylation and saponification procedures ofExample 41, but using methyl 2-phenyl-3-indolinyl acetate in place ofmethyl [3-(3-indolinyl)-propionate hydrochloride givesl-pchlorobenzoyl-2-phenyl-2,3-dihydro-3-indolylacetic acid.

EXAMPLE 66 Sodium ,8 (1 p-chlorobenzoyl-5-meth0xy-2,3-dihydr0-3-indolylpropionate fl 1 p-chlorobenZoyl-5-methoxy-2,3-dihydro-3-indolylpropionic acid (0.01 mole) in ml. ethanol is added to a solution ofsodium hydroxide (0.01 mole) in 25 ml. water at room temperature. Themixture is stirred for a few minutes and then evaporated in vacuo togive sodium [3 (1 p chlorobenzoyl 5-methoXy-2,3-dihydro-3-indolylpropionate.

EXAMPLE 67 Dicyclohexylcarbodiimide (0.0054 mole) in 6 ml. anhydroustetrahydrofuran is added to a solution of ,B-(I-pchlorobenzoyl 5methoxy-2,3-dihydro-3-indolyl)-pr0pionic acid (0.005 mole) andB-diethylaminoethanol (0.0052 mole) in 23 ml. anhydrous tetrahydrofuranand the mixture shaken vigorously for one minute. After sitting over aweekend, stoppered, the mixture is filtered to removeN,N'-dicyclohexylurea and ca. twenty drops of glacial acetic acid isadded to decompose any remaining carbodiimide. After sitting two hours,the mixture is filtered, 250 ml. of ether is added, and the resultingsolution extracted with 2 X 250 ml. 2.5 N hydrochloric acid. Thecombined acid extractions are washed with 2 x 250 ml. ether and thenice-bath cooled and made slightly alkaline with concentrated ammoniumhydroxide. The aqueous mixture is then extracted with 2 x 250 ml. ofether, and the combined ether extractions Washed with 10 x 200 ml. ofwater and dried over anhydrous potassium carbonate. After filtering, theether is removed in vacuo to give B'-diethylaminoethylfi-(l-p-chlorobenzoyl- 5 -methoxy2,3 -dihydro-3-indolyl) -propionate.

When fi-diethylaminoethanol in the above example is replaced by anequivalent amount of benzyl alcohol, phenol, p-chlorophenol andphenethyl alcohol the corresponding benzyl, phenyl, p-chlorophenyl andfi-phenylethyl esters of{i-(1-p-chlorobenzoyl-5-methoxy-2,3-dihydro-3-indolyl)-propionic acidare obtained.

EXAMPLE 68 ,8-(1-p-chlorobenzoyI-S-methoxy-Z,3-dihydr0-3-indolyl)propionmo'rpholide Isobutylchloroformate (0.0075 mole) is added to astirred, ice-cooled solution of fi-(l-p-chlorobenzoyl-S-methoxy-Z,3-dihydro-3-indolyl)-propionic acid (0.0074 mole) andtriethylamine (0.0075 mole) in 40 ml. of 1,2-dimethoxyethane. Afterstirring, cold, under a nitrogen atmosphere for 20 minutes, the mixtureis suction filtered and the filtrate immediately set under nitrogen andice-cooled again. At this time 0.008 mole of morpholine in 10 ml. of1,2-dimethoxyethane is added, and the mixture stirred at ca. 5 C.overnight. The mixture is then poured into 250 ml. of chloroform and thechloroform solution washed with 2 x 200 ml. 2.5 N hydrochloric acid, 1 x100 ml. water, 2 x 200 ml. saturated sodium bicarbonate solution, 200ml. portions of water until the washings are neutral, and then driedover anhydrous sodium sulfate. Concentration in vacuo of the solution toa small volume followed by chromatography on a 100 g. acid-washedalumina column using etherpetroleum ether as eluent (v./v. 20100%) givesfl-(lp chlorobenzoyl -methoxy-2,3-dihydro-3-indolyl)-propionmorpholide.

When morpholine in the above example is replaced by an equivalent amountof butylamine, fi-hydroxyethylamine, diphenylamine, dibenzylamine,B-phenethylamine, aniline, m-trifluoromethylaniline and diethylamine,the corresponding amides of ,8-(1-p-chlorobenzoyl-S-methoxy-2,3-dihydro-3-indolyl)propionic acid are thus obtained.

EXAMPLE 69 'y-(1-p-chlorobenzoyl-2,3-dihydr0-3-ind0lyl)- a-aminobutyricacid Methyl 'y (1 p-chlorobenzoyl-Z,3-dihydro-3-indolyl)- a-ketobutyrate(0.01 mole), prepared via a literature procedure for the correspondingdes-chloro analog, hydroxylamine hydrochloride (0.02 mole), 200 ml.ethanol and 50 ml. pyridine are refluxed under nitrogen for six hours.After cooling, the mixture is concentrated in vacuo to ca. 50 ml. andpoured into 1 l. of an ice-water mixture with vigorous stirring. Afterthe ice melts, the aqueous layer is poured ofi? the residue, the residueextracted with ca. 500 ml. ethyl acetate, and the ethyl acetate solutiondried over anhydrous sodium sulfate. After filtering, the solvent isremoved in vacuo, the residue taken up in 150 ml. of anhydrous methanol,and the solution reduced in the presence of 3 g. of 5% palladium oncarbon at room temperature under a hydrogen pressure of 40 psi. Afterfiltering, the solution is concentrated in vacuo to ca. 25 ml., and 500ml. of 2.5 N hydrochloric acid is added. The aqueous system is thenwashed with 3 x 150 ml. chloroform, made slightly alkaline withconcentrated ammonium hydroxide, and extracted with 3 x 150 ml.chloroform. The combined chloroform extracts are then washed with 150ml. portions of water until netural, dried over anhydrous potassiumcarbonate, filtered and the chloroform removed in vacuo to give methyl'y-(l-pchlorobenzoyl-2,3-dihydro-3-indolyl x-aminobutyrate.

The above ester (0.001 mole) is suspended in ml. of water with vigorousstirring, and potassium hydroxide (0.001 mole) in 2 ml. of water isadded. When solution is obtained, the aqueous system is filtered andcarefully neutralized with 1.25 N hydrochloric acid. Decantation of theaqueous phase followed by several water rinses and drying in a vacuumdessicator over anhydrous calcium chloride gives 7 (1 pchlorobenzoyl-2,3-dihydro-3-indolyl)-ix-aminobutyric acid.

EXAMPLE 70 'y- (1 -p-chl0r0benz0yl-2,3-dihydr0-3-ind0lyl) -a-methoxybutyric acid Methyl 'y (1 p-chlorobenzoyl-2,3-dihydro-3-indolyl)-a-hydroxybutyric acid (0.001 mole), prepared by reduction with sodiumborohydride of the corresponding ketone (Example 69) via a literatureprocedure, methyl iodide (0.002 mole), sodium iodide (0.001 mole) and 3g. anhydrous potassium carbonate in 40 ml. of methanol are greatlyrefluxed under nitrogen, the reaction mixture cooled, filtered and themethanol and excess methyl iodide removed in vacuo. The residue istriturated with 50 ml. ether, the ether solution filtered, concentratedin vacuo to ca. 10 ml., charged onto a 100 g. acid-washed alumina columnand eluted With ether petroleum ether (v./v. -75") to give methyl'y-(1-p-chlorobenz0yl-2,3- dihydro 3 indolyl)-ix-methoxybutyrate.Saponification and purification of the above ester following theprocedures set forth in Example 41 gives 'y-(l-p-chlorobenzoyl-2,3-dihydro-3-indolyl) -a-methoxybutyric acid.

30 EXAMPLE 71 Ethyl 2-melhyl-5-meth0xy-2,3-dihydr0-3-ind0lylacetate Amixture of ethyl 2-methyl-5-methoxy-3-indolylacetate (0.077 mole) and 20g. of mossy tin in 200 ml. of 6 N hydrochloric acid is heated underreflux for 18 hours. The solution is filtered and concentrated in vacuoto a volume of about 50 ml. Ethanol is added and the evaporationrepeated in order to remove water. The residue is then treated with 200ml. of 2 N ethanolic hydrogen chloride and the mixture refluxed for 18hours. The solution is concentrated in vacuo to 50 ml., diluted with 300ml. of water, and extracted with 200 ml. of ether. The aqueous solutionis made alkaline with 2.5 N sodium hydroxide and filtered. The filtrateis extracted with 2 x 300 ml. of ether, washed with ml. of water, driedover anhydrous potassium carbonate, filtered and evaporated in vacuo togive ethyl 2 methyl 5-methoxy-2,3-dihydro-3-indolylacetate.

EXAMPLE 72 Ethyl 1-benzoyI-S-meth0xy-2-methyl-2,3-dihydro-3-indolylacetate To a solution of 0.007 mole of ethyl 5-methoxy-2--methyl-2,3-dihydro-3-indolyl acetate in 20 ml. of pyridine is added 3ml. of benzoyl chloride with ice cooling and stirring. After 2 hours inthe ice-bath the reaction mixture is allowed to stand at roomtemperature for 4 hours. The mixture is then poured into 100 ml. oficed-water and extracted with 2 x 100 ml. ether. The ethereal solutionis Washed with 2 x 100 ml. water, dilute hydrochloric acid, dilutesodium bicarbonate and water successively and dried over sodium sulfate.Evaporation of the solvent and recrystallization of the residual solidfrom benzene-Skellysolve B gives ethyl 1-benzoyl-5-methoxy-2-methyl-2,3-dihydro-3-indolylacetate, M.P. 85.586.5 C.

U.V. absorption: A 2420, 2720, E% 222, 317.

EXAMPLE 73 1-benz0yl-5-methoxy-2-methyl-2,3-dihydr0-3-indolyl aceticacid The ethyl ester of the above acid is dissolved in a mixture of 18ml. ethanol and 2 ml. 11 N sodium hydroxide at room temperature. Afterstanding for 18 hours the solution is concentrated in vacuo to ca. /2volume, diluted with water and extracted with ether to remove anyneutral material. The aqueous solution is acidified with dilutehydrochloric acid and then extracted with ether. The ether solution isdried over sodium sulfate and evaporated to dryness. The residue isrecrystallized from benzene- Skellysolve B, M.P. -186 C.

EXAMPLE 74 6.5 g. (0.02 mole) of ,B-(1-benzoyl-2,3-dihydro-3-indolyl)propionic acid is added to 50 ml. of water which has been flushed withnitrogen. The slurry is stirred under nitrogen and 20 ml. of 1.05 Nsodium carbonate added with stirring. When a clear solution is obtained,a solution of 2.2 g. of Al (SO -18H O in 8 ml. of water is added withvigorous stirring. The mixture is stirred until it is homogenous and thesolid aluminum salt of (l-benzoyl-2,3-dihydro-3-indolyl) propionic acid,is recovered by filtration and washed with water and with ethanol.

In a similar fashion, there may be prepared the sodium and aluminumsalts as well as other salts, such as the potassium, iron and magnesiumsalts, of the various (3-indolyl)aliphatic acids described in theaccompanying examples.

I claim:

1. A method of treating inflammation and fever due to inflammation, inpatients, which comprises orally adminn '9 91 final istering, to saidpatients, 1.04000 mg. per day of a com- 4. The method according to claim1 in which the compound of the structure pound is ca[1-p-ch1orobenZoyl-2-n1etl1yl-S-1ncthoxy-3- H indolinylJpropionic acid.

I 5 References Cited by the Examiner R2 UNITED STATES PATENTS N2,994,640 8/1961 Zellner 16765 1 H 00 3,006,812 10/1961 Wallace l67653,047,585 7/1962 Johnson 260319 ,1, 10 3,075,993 1/1963 Chemcrda et a1.2603l9 w 3,161,654 12/1964 Sheri 167-65 R 15 halophenyl; R is selectedfrom the group consisting of hydrogen OTHER REFERENCES and lower alkyl;British Med. 1., vol. 2, No. 5402, page 429, August X is selected fromthe group consisting of a-propionic 1 acid, fl-propionic acid and aceticacid; R is selected from the group consisting of hydrogen and SA ROSPrimary lower alkoxy. 2. The method of claim 1 in which the compound isNICHOLAS RIZZO {3-(1-benZoyl-5-meth0Xy-3-ind01inyl)propionic acid. 20MARY U. OBRIEN, JEROME D. GOLDBERG,

3. The method of claim 11 in which the compound is Assistant Examiners.l-p-chloro benzoyl-Z-methyl-S-methoxy-3-indolinyl acetic acid.

1964. Chemical Abstracts 58: 113140 (1963).

1. A METHOD OF TREATING INFLAMMATION AND FEVER DUE TO INFLAMMATION, INPATIENTS, WHICH COMPRISES ORALLY ADMINISTERING, TO SAID PATIENTS,1.0-4000 MG. PER DAY OF A COMPOUND OF THE STRUCTURE